DESCRIPTION
TITLE OF INVENTION: TRICYCLIC COMPOUND AND JAK INHIBITOR
TECHNICAL FIEL5 D
The present invention relates to novel tricyclic compounds having JAK inhibitory
activities.
BACKGROUND ART
10 The JAK (Janus kinase) family is a tyrosine kinase family consisting of four
members, JAK1, JAK2, JAK3 and Tyk (Tyrosine kinase) 2 and plays an important role in
cytokine signaling by phosphorylating STATs (signal transducers and activators of
transcription).
Analyses of JAK1 knockout mice and JAK1-deficient cells suggest involvement of
15 JAK1 in various receptor-mediated signaling pathways such as IFN (Interferon), IFN,
IFN, IL (interleukin)-2, IL-4, IL-6, IL-7 and IL-15 signaling (Non-Patent Document 1).
Therefore, regulation of inflammatory responses via these signaling pathways is
therapeutically promising for treatment of diseases involving macrophage and
lymphocyte activation such as autoimmune diseases and acute and chronic organ
20 transplant rejection.
Analyses of JAK2 knockout mice and JAK2-deficient cells suggest involvement of
JAK2 in various receptor-mediated signaling pathways such as EPO (Erythropoietin),
TPO (thrombopoietin), IFN, IL-3 and GM-CSF (Granulocyte Macrophage colonystimulating
Factor) signaling (Non-Patent Documents 2, 3 and 4). These signaling
25 pathways are supposed to mediate differentiation of erythrocyte or thrombocyte
progenitor cells in bone marrow.
Meanwhile, it is suggested that a substitution of phenylalanine-617 with valine in
JAK2 is associated with myeloproliferative diseases (Non-Patent Document 2).
Therefore, regulation of differentiation of myeloid progenitor cells via these mechanisms
30 is therapeutically promising for treatment of chronic myeloproliferative diseases.
JAK3 plays an important role in various receptor-mediated signaling pathways
such as IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 signaling by noncovalently associating with
2
the common chain (Non-Patent Documents 5 and 6).
Lowered JAK3 protein levels or defects in the common chain gene observed in
patients with an immunodeficiency called X-linked Severe Combined Immuno
Deficiency (XSCID) suggest that blocking of the JAK3 signaling pathway leads to
immunosuppression (Non-Patent Documents 7 and 8)5 .
Animal experiments indicate the importance of JAK3 not only in maturation of Band
T-lymphocytes but also in maintenance of T-lymphocyte functions. Therefore,
regulation of immune responses via this mechanism is a promising therapy for T-cell
lymphoproliferative diseases such as organ transplant rejection and autoimmune
10 diseases.
In leukemia and lymphoma cells and cells of many solid cancers, JAKs and
STATs are activated constitutively (Non-Patent Document 9). This indicates that JAK
inhibitors are expected to cure cancer and leukemia by suppressing cancer cell growth.
The JAK inhibitor CP-690, 550 is reported to have improved the pathology of
15 rheumatoid arthritis and psoriasis in clinical tests (Non-Patent Documents 10 and 11)
and suppressed rejection in a monkey model of kidney transplantation and airway
inflammation in a murine asthma model (Non-Patent Documents 12 and 13).
From these findings, immunosuppression by JAK inhibitors is considered to be
useful for prevention or treatment of organ transplant rejection and post-transplant graft20
versus-host reaction, autoimmune diseases and allergic diseases. Although
compounds having JAK inhibitory action other than CP-690, 550 have been reported
(Patent Documents 1 to 15), development of more of such compounds is demanded.
Patent Document 15 reports some tricyclic heterocyclic compounds having JAK
inhibitory action, but has no specific description of the compounds of the present
25 invention.
PRIOR ART DOCUMENTS
PATENT DOCUMENTS
Patent Document 1: WO2001/042246
30 Patent Document 2: WO2007/007919
Patent Document 3: WO2007/077949
Patent Document 4: WO2008/084861
3
Patent Document 5: WO2009/152133
Patent Document 6: WO2010/119875
Patent Document 7: WO2011/045702
Patent Document 8: WO2011/068881
Patent Document 9: WO2011/068895 9
Patent Document 10: WO2011/075334
Patent Document 11: WO2011/086053
Patent Document 12: WO2012/085176
Patent Document 13: WO2012/127506
10 Patent Document 14: WO2012/149280
Patent Document 15: WO2013/024895
NON-PATENT DOCUMENTS
Non-Patent Document 1: J. Immunol., 2007, 178, pp. 2623-2629
Non-Patent Document 2: Pathol. Biol., 2007, 55, pp. 88-91
15 Non-Patent Document 3: Cancer Genet. Cytogenet., 2009, 189, pp. 43-47
Non-Patent Document 4: Semin. Cell. Dev. Biol., 2008, 19, pp. 385-393
Non-Patent Document 5: Cell, 2002, 109, pp. S121-131
Non-Patent Document 6: Science, 2002, 298, pp., 1630-1634
Non-Patent Document 7: Nature, 1995, 377, pp. 65-68
20 Non-Patent Document 8: Science, 1995, 270, pp. 797-800
Non-Patent Document 9: JAK-STAT.,2013, 2, e23828
Non-Patent Document 10: Arthritis Rheum., 2009, 60, pp. 1895-1905
Non-Patent Document 11: J Invest. Dermatol., 2009, 129, pp. 2299-2302
Non-Patent Document 12: Science, 2003, 302, pp. 875-878
25 Non-Patent Document 13: Eur. J. Pharmacol., 2008, 582, pp. 154-161
DISCLOSURE OF THE INVENTION
TECHNICAL PROBLEM
The object of the present invention is to provide novel drug compounds having
30 excellent JAK inhibitory activities useful for prevention, treatment or improvement of
autoimmune diseases, inflammatory diseases and allergic diseases.
4
SOLUTION TO PROBLEMS
As a result of their extensive research in search of new low-molecular-weight
compounds having JAK inhibitory activities, the present inventors discovered that the
compounds of the present invention have high inhibitory activities on cytokine signaling
via the JAK family in rat or human whole blood and accomplished the present invention5 .
Namely, the present invention provides the following.
(1) A compound represented by the formula (I):
[wherein A1 is a C3-7 cycloalkylene group, L1 is a C1-6 alkylene group, X1 is O or NH, and
10 when X1 is O, R1 is a C1-6 haloalkyl group, a cyano C1-6 haloalkyl group or a cyano C1-6
alkyl group, and when X1 is NH, R1 is a cyano C1-6 haloalkyl group or a cyano C1-6 alkyl
group], a tautomer or pharmaceutically acceptable salt of the compound or a solvate
thereof.
(2) The compound according to (1), wherein L1 is a methylene group, a tautomer or
15 pharmaceutically acceptable salt of the compound or a solvate thereof.
(3) The compound according to (1) or (2), wherein A1 is a cyclohexanediyl group, a
tautomer or pharmaceutically acceptable salt of the compound or a solvate thereof.
(4) The compound according to any one of (1) to (3), wherein X1 is O, a tautomer or
pharmaceutically acceptable salt of the compound or a solvate thereof.
20 (5) The compound according to (4), wherein R1 is a C1-4 haloalkyl group, a tautomer
or pharmaceutically acceptable salt of the compound or a solvate thereof.
(6) The compound according to (4), wherein R1 is a 3,3,3-trifluoropropyl group, a
tautomer or pharmaceutically acceptable salt of the compound or a solvate thereof.
(7) 1-{trans-4-[(3,3,3-Trifluoropropoxy)methyl]cyclohexyl}-1H25
pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione, a tautomer or
pharmaceutically acceptable salt of the compound or a solvate thereof.
(8) The compound according to any one of (1) to (3), wherein X1 is NH, a tautomer or
pharmaceutically acceptable salt of the compound or a solvate thereof.
(9) The compound according to (8), wherein R1 is a cyano C1-4 haloalkyl group, a
5
tautomer or pharmaceutically acceptable salt of the compound or a solvate thereof.
(10) The compound according to (8), wherein R1 is a 3-cyano-1,1,1-trifluoropropan-2-yl
group, a tautomer or pharmaceutically acceptable salt of the compound or a solvate
thereof.
(11) 3-({[trans-4-(2,4-Dioxo-2,3,4,7-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,35 -
d]pyrimidin-1-yl)cyclohexyl]methyl}amino)-4,4,4-trifluorobutanenitrile, a tautomer or
pharmaceutically acceptable salt of the compound or a solvate thereof.
(12) (R)-3-({[trans-4-(2,4-Dioxo-2,3,4,7-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-
d]pyrimidin-1-yl)cyclohexyl]methyl}amino)-4,4,4-trifluorobutanenitrile, a tautomer or
10 pharmaceutically acceptable salt of the compound or a solvate thereof.
(13) A compound represented by the formula (II):
[wherein A2 is a C3-7 cycloalkylene group, L2 is a C1-6 alkylene group, and R2 is a 5 to
10-membered aromatic heterocyclic group (the heterocyclic group may be substituted
15 with one or two identical or different substituents independently selected from the group
consisting of halogen atoms, C1-4 alkyl groups and C1-4 haloalkyl groups)], a tautomer or
pharmaceutically acceptable salt of the compound or a solvate thereof.
(14) The compound according to (13), wherein L2 is a methylene group, a tautomer or
pharmaceutically acceptable salt of the compound or a solvate thereof.
20 (15) The compound according to (13) or (14), wherein A2 is a cyclohexanediyl group, a
tautomer or pharmaceutically acceptable salt of the compound or a solvate thereof.
(16) The compound according to any one of (13) to (15), wherein R2 is a 5 to 6-
membered nitrogen-containing aromatic heterocyclic group (the heterocyclic group may
be substituted with one or two identical or different substituents independently selected
25 from the group consisting of halogen atoms, methyl groups and trifluoromethyl groups),
a tautomer or pharmaceutically acceptable salt of the compound or a solvate thereof.
(17) The compound according to any one of (13) to (16), wherein R2 is a pyrazolyl
group (the pyrazolyl group may be substituted with one or two identical or different
substituents independently selected from the group consisting of halogen atoms, methyl
6
groups and trifluoromethyl groups), a tautomer or pharmaceutically acceptable salt of
the compound or a solvate thereof.
(18) 1-{trans-4-[(4-Methyl-1H-pyrazol-1-yl)methyl]cyclohexyl}-1H-pyrrolo[2,3-
h][1,6]naphthyridin-4(7H)-one, a tautomer or pharmaceutically acceptable salt of the
compound or a solvate thereof5 .
(19) A compound represented by the formula (III):
[wherein A3 is a C3-7 cycloalkylene group, L3 is a C1-6 alkylene group, X3 is O or NH, and
when X3 is O, R3 is a C1-6 haloalkyl group, a cyano C1-6 haloalkyl group or a cyano C1-6
10 alkyl group, and when X3 is NH, R3 is a cyano C1-6 haloalkyl group or a cyano C1-6 alkyl
group], a tautomer or pharmaceutically acceptable salt of the compound or a solvate
thereof.
(20) The compound according to (19), wherein L3 is a methylene group, a tautomer or
pharmaceutically acceptable salt of the compound or a solvate thereof.
15 (21) The compound according to (19) or (20), wherein A3 is a cyclohexanediyl group, a
tautomer or pharmaceutically acceptable salt of the compound or a solvate thereof.
(22) The compound according to any one of (19) to (21), wherein X3 is O, a tautomer
or pharmaceutically acceptable salt of the compound or a solvate thereof.
(23) The compound according to (22), wherein R3 is a C1-4 haloalkyl group or a cyano
20 C1-4 haloalkyl group, a tautomer or pharmaceutically acceptable salt of the compound or
a solvate thereof.
(24) The compound according to (22), wherein R3 is a 2,2,2-trifluoroethyl group or a
3,3,3-trifluoropropyl group, a tautomer or pharmaceutically acceptable salt of the
compound or a solvate thereof.
25 (25) The compound according to (22), wherein R3 is a 3-cyano-1,1,1-trifluoropropan-2-
yl group or a 2-cyano-1,1,1-trifluoropropan-2-yl group, a tautomer or pharmaceutically
acceptable salt of the compound or a solvate thereof.
(26) 1-{trans-4-[(2,2,2-Trifluoroethoxy)methyl]cyclohexyl}-1H-pyrrolo[2,3-
h][1,6]naphthyridin-4(7H)-one, a tautomer or pharmaceutically acceptable salt of the
7
compound or a solvate thereof.
(27) 1-{trans-4-[(3,3,3-Trifluoropropoxy)methyl]cyclohexyl}-1H-pyrrolo[2,3-
h][1,6]naphthyridin-4(7H)-one, a tautomer or pharmaceutically acceptable salt of the
compound or a solvate thereof.
(28) 4,4,4-Trifluoro-3-{[trans-4-(4-oxo-4,7-dihydro-1H-pyrrolo[2,3-h][1,6]naphthyridin-5 1-
yl)cyclohexyl]methoxy}butanenitrile, a tautomer or pharmaceutically acceptable salt of
the compound or a solvate thereof.
(29) (R)-4,4,4-Trifluoro-3-{[trans-4-(4-oxo-4,7-dihydro-1H-pyrrolo[2,3-
h][1,6]naphthyridin-1-yl)cyclohexyl]methoxy}butanenitrile, a tautomer or
10 pharmaceutically acceptable salt of the compound or a solvate thereof.
(30) The compound according to any one of (19) to (21), wherein X3 is NH, a tautomer
or pharmaceutically acceptable salt of the compound or a solvate thereof.
(31) The compound according to (30), wherein R3 is a cyano C1-4 haloalkyl group, a
tautomer or pharmaceutically acceptable salt of the compound or a solvate thereof.
15 (32) The compound according to (30), wherein R3 is a 3-cyano-1,1,1-trifluoropropan-2-
yl group, a tautomer or pharmaceutically acceptable salt of the compound or a solvate
thereof.
(33) 4,4,4-Trifluoro-3-({[trans-4-(4-oxo-4,7-dihydro-1H-pyrrolo[2,3-h][1,6]naphthyridin-1-
yl)cyclohexyl]methyl}amino)butanenitrile, a tautomer or pharmaceutically acceptable salt
20 of the compound or a solvate thereof.
(34) (R)-4,4,4-Trifluoro-3-({[trans-4-(4-oxo-4,7-dihydro-1H-pyrrolo[2,3-
h][1,6]naphthyridin-1-yl)cyclohexyl]methyl}amino)butanenitrile, a tautomer or
pharmaceutically acceptable salt of the compound or a solvate thereof.
(35) A JAK inhibitor containing the compound as defined in any one of (1) to (34), a
25 tautomer or a pharmaceutically acceptable salt of the compound or a solvate thereof, as
an active ingredient.
(36) A preventive, therapeutic or improving agent for diseases against which inhibition
of JAK is effective, which contains the compound as defined in any one of (1) to (34), a
tautomer or pharmaceutically acceptable salt of the compound or a solvate thereof, as
30 an active ingredient.
(37) A therapeutic agent for rheumatoid arthritis, which contains the compound as
defined in any one of (1) to (34), a tautomer or pharmaceutically acceptable salt of the
8
compound or a solvate thereof, as an active ingredient.
(38) Medicament containing the compound as defined in any one of (1) to (34), a
tautomer or a pharmaceutically acceptable salt of the compound or a solvate thereof, as
an active ingredient.
5
ADVANTAGEOUS EFFECT(S) OF INVENTION
The present invention has made it possible to provide novel tricyclic compounds
which have excellent JAK inhibitory action and are especially useful for prevention,
treatment or improvement of autoimmune diseases, inflammatory diseases and allergic
diseases10 .
DESCRIPTION OF EMBODIMENT(S)
Now, the present invention will be described in further detail.
In the present invention, “n-” denotes normal, “i-” denotes iso, “s-” and "sec"
15 denote secondary, “t-” and “tert-” denote tertiary, “c-” denotes cyclo, “o-” denotes ortho,
“m-” denotes meta, “p-” denotes para, “cis-” denotes a cis isomer, “trans-” denotes a
trans isomer, “rac” and “racemate” denote racemate, “Ph” denotes phenyl, “Py” denotes
pyridyl, “Me” denotes methyl, “Et” denotes ethyl, “Pr” denotes propyl, “Bu” denotes butyl,
“Boc” denotes tertiary-butoxycarbonyl, “Ms” denotes methanesulfonyl, “Tf” denotes
20 trifluoromethanesulfonyl, “Ts” denotes p-toluenesulfonyl, “SEM” denotes [2-
(trimethylsilyl)ethoxy]methyl, “TIPS” denotes triisopropylsilyl, “TMS” denotes
trimethylsilyl, and “Ac” denotes acetyl.
First, the terms used herein for description of chemical structures will be explained.
A “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine
25 atom.
A “C1-4 alkyl group” is a methyl group, an ethyl group, a n-propyl group, an
isopropyl group, a n-butyl group, an isobutyl group, a s-butyl group or a t-butyl group.
A “C1-6 alkyl group” is a linear or branched alkyl group containing one to six carbon
atoms, and in addition to the above-mentioned specific “C1-4 alkyl group”, a n-pentyl
30 group, n-hexyl group or the like may be mentioned.
A “cyano C1-6 alkyl group” is a group derived from the above-mentioned “C1-6 alkyl
group” by replacing one or more hydrogen atom(s) at arbitrary position(s) by one or
9
more cyano groups. As specific examples, a cyanomethyl group, a 2-cyanoethyl group,
a 1-cyanopropan-2-yl group, a 2-cyanopropan-2-yl group, a 3-cyanopropyl group, a 1,3-
dicyanopropan-2-yl group, a 1-cyanobutan-2-yl group, a 4-cyanobutyl group, a 5-
cyanopentyl group, a 6-cyanohexyl group and the like may be mentioned.
A “C1-4 haloalkyl group” is a group derived from the above-mentioned “C1-4 al5 kyl
group” by replacing one or more hydrogen atom(s) at arbitrary position(s) by one or
more identical or different halogen atoms selected from the group consisting of fluorine
atom, chlorine atom, bromine atom and iodine atom. As specific examples, a
trifluoromethyl group, a pentafluoroethyl group, a 2,2,2-trifluoroethyl group, a 3,3,3-
10 trifluoropropyl group, a 4,4,4-trifluorobutyl group, a 4,4,4-trifluorobutan-2-yl group, a 2,2-
difluoroethyl group, a 2,2-difluoropropyl group, a 2-chloroethyl group, a 3-bromopropyl
group, a 4-iodobutyl group and the like may be mentioned.
A “C1-6 haloalkyl group” is a group derived from the above-mentioned “C1-6 alkyl
group” by replacing one or more hydrogen atom(s) at arbitrary position(s) by one or
15 more identical or different halogen atoms selected from the group consisting of fluorine
atom, chlorine atom, bromine atom and iodine atom. As specific examples, in addition
to the above-mentioned specific “C1-4 haloalkyl group”, a 5,5,5-trifluoropentyl group, a
6,6,6-trifluorohexyl group, a 5-chloropentyl group, a 6-bromohexyl group and the like
may be mentioned.
20 A “cyano C1-4 haloalkyl group” is a group derived from the above-mentioned “C1-4
haloalkyl group” by replacing one or more hydrogen atom(s) at arbitrary position(s) by
one or more cyano groups. As specific examples, a 1-cyano-2,2,2-trifluoroethyl group,
a 3-cyano-1,1,1-trifluoropropan-2-yl group, a 2-cyano-1,1,1-trifluoropropan-2-yl group, a
4-cyano-1,1,1-trifluorobutan-2-yl group and the like may be mentioned.
25 A “cyano C1-6 haloalkyl group” is a group derived from the above-mentioned “C1-6
haloalkyl group” by replacing one or more hydrogen atom(s) at arbitrary position(s) by
one or more cyano groups. As specific examples, in addition to the above-mentioned
specific “cyano C1-4 haloalkyl group”, a 5-cyano-1,1,1-trifluoropentan-2-yl group, a 6-
cyano-1,1,1-trifluorohexan-2-yl group and the like may be mentioned.
30 A “C3-7 cycloalkane” is a monocyclic, fused, bridged or spiro aliphatic hydrocarbon
ring having 3 to 7 ring-constituting carbon atoms. As specific examples, cyclopropane,
cyclobutane, cyclopentane, cyclohexane, cycloheptane, bicyclo[2.2.1]heptane and the
10
like may be mentioned.
A “C3-7 cycloalkyl group” is a monovalent group derived from the above-mentioned
“C3-7 cycloalkane” by removing a hydrogen atom at an arbitrary position. As specific
examples, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl
group, a cycloheptyl group, a bicyclo[2.2.1]heptan-1-yl group, a bicyclo[2.2.1]heptan-5 2-
yl group, a bicyclo[2.2.1]heptan-7-yl group and the like may be mentioned.
A “C1-6 alkylene group” is a bivalent group derived from the above-mentioned “C1-6
alkyl group” by removing a hydrogen atom at an arbitrary position. As specific
examples, a methylene group, an ethylene group, a propane-1,3-diyl group, a propane-
10 1,2-diyl group, a 2,2-dimethylpropane-1,3-diyl group, a hexane-1,6-diyl group, a 3-
methylbutane-1,2-diyl group and the like may be mentioned.
A “C3-7 cycloalkylene group” is a bivalent group derived from the above-mentioned
“C3-7 cycloalkyl group” by removing a hydrogen atom at an arbitrary position. As
specific examples, a cyclopropane-1,2-diyl group, a cyclobutane-1,3-diyl group, a
15 cyclopentane-1,3-diyl group, a cyclohexane-1,4-diyl group, a cyclohexane-1,3-diyl group,
a cyclopentane-1,4-diyl group and the like may be mentioned.
A “5 to 10-membered aromatic heterocyclic ring” is a monocyclic or fused aromatic
heterocyclic group having 5 to 10 ring-constituting atoms including carbon atoms and
one or more hetero atoms (such as nitrogen atoms, oxygen atoms or sulfur atoms). As
20 specific examples, furan, thiophene, pyrrole, imidazole, triazole, tetrazole, thiazole,
pyrazole, oxazole, isoxazole, isothiazole, thiadiazole, oxadiazole, pyridine, pyrazine,
pyridazine, pyrimidine, triazine, purine, pteridine, quinoline, isoquinoline, naphthylidine,
quinoxaline, cinnoline, quinazoline, phthalazine, imidazopyridine, imidazothiazole,
imidazooxazole, benzothiazole, benzoxazole, benzimidazole, indole, pyrrolopyridine,
25 thienopyridine, furopyridine, benzothiadiazole, benzoxadiazole, pyridopyrimidine,
benzofuran, benzothiophene, thienofuran and the like may be mentioned.
In the case of a “5 to 10-membered aromatic heterocyclic ring” having a C=N
double bond, it may be in the form of an N-oxide.
A “5 to 10-membered aromatic heterocyclic group” is a monovalent group derived
30 from the above-mentioned “5 to 10-membered aromatic heterocyclic ring” by removing a
hydrogen atom at an arbitrary position.
A “5 to 6-membered aromatic heterocyclic ring” is a monocyclic group having 5 or
11
6 ring-constituting atoms among the above-mentioned “5 to 10-membered aromatic
heterocyclic ring”. As specific examples, pyrrole, pyrazole, imidazole, triazole,
tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, furan, thiophene, thiazole,
isothiazole, oxazole, isoxazole, oxadiazole, thiadiazole and the like may be mentioned.
A “nitrogen-containing 5 to 6-membered aromatic heterocyclic ring” is an aromati5 c
heterocyclic ring having one or more nitrogen atoms as ring-constituting atoms among
the above-mentioned “5 to 6-membered aromatic heterocyclic ring”. As specific
examples, pyrrole, pyrazole, imidazole, triazole, tetrazole, pyridine, pyridazine,
pyrimidine, pyrazine, triazine, thiazole, isothiazole, oxazole, isoxazole, oxadiazole,
10 thiadiazole and the like may be mentioned.
A “nitrogen-containing 5 to 6-membered aromatic heterocyclic group” is a
monovalent group derived from the above-mentioned “nitrogen-containing 5 to 6-
membered aromatic heterocyclic ring” by removing a hydrogen atom at an arbitrary
position.
15 Next, preferred structures of the respective substituents in the present invention
will be mentioned.
A1 is preferably a cyclopentanediyl group, a cyclohexanediyl group or a
cycloheptanediyl group, more preferably a cyclohexanediyl group, further preferably a
cyclohexane-1,4-diyl group.
20 L1 is preferably a methylene group or an ethylene group, more preferably a
methylene group.
X1 is preferably O or NH.
When X1 is O, R1 is preferably a 2,2,2-trifluoroethyl group, a 3,3,3-trifluoropropyl
group, a 3-cyano-1,1,1-trifluoropropan-2-yl group or a 2-cyano-1,1,1-trifluoropropan-2-yl
25 group, more preferably a 3,3,3-trifluoropropyl group.
When X1 is NH, R1 is preferably a 3-cyano-1,1,1-trifluoropropan-2-yl group or a 1-
cyanopropan-2-yl group, more preferably a 3-cyano-1,1,1-trifluoropropan-2-yl group.
A2 is preferably a cyclopentanediyl group, a cyclohexanediyl group or a
cycloheptanediyl group, more preferably a cyclohexanediyl group, further preferably a
30 cyclohexane-1,4-diyl group.
L2 is preferably a methylene group or an ethylene group, more preferably a
methylene group.
12
R2 is preferably a pyrrolyl group, a thienyl group, a furyl group, a pyrazolyl group,
an imidazolyl group, a thiazolyl group, an isothiazolyl group, an oxazolyl group, an
isoxazolyl group, a 1H-1,2,4-triazolyl group, a 4H-1,2,4- triazolyl group, a pyridyl group,
a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group or a 1,3,5-triazinyl group
(each of the pyrrolyl group to the 1,3,5-triazinyl group may be substituted with one o5 r
two identical or different substituents independently selected from the group consisting
of halogen atoms, methyl groups and trifluoromethyl groups), more preferably a
pyrazolyl group, an imidazolyl group, a thiazolyl group, an isothiazolyl group, an
oxazolyl group or an isoxazolyl group (each of the pyrazolyl group to the isoxazolyl
10 group may be substituted with one or two identical or different substituents
independently selected from the group consisting of halogen atoms, methyl groups and
trifluoromethyl groups), further preferably a pyrazolyl group (the pyrazolyl group may be
substituted with one or two identical or different substituents independently selected
from the group consisting of halogen atoms, methyl groups and trifluoromethyl groups),
15 particularly preferably a pyrazolyl group substituted with a methyl group.
A3 is preferably a cyclopentanediyl group, a cyclohexanediyl group or a
cycloheptanediyl group, more preferably a cyclohexanediyl group, further preferably a
cyclohexane-1,4-diyl group.
L3 is preferably a methylene group or an ethylene group, more preferably a
20 methylene group.
X3 is preferably O or NH.
When X3 is O, R3 is preferably a 2,2,2-trifluoroethyl group, a 3,3,3-trifluoropropyl
group, a 3-cyano-1,1,1-trifluoropropan-2-yl group or a 2-cyano-1,1,1-trifluoropropan-2-yl
group.
25 When X3 is NH, R3 is preferably a 3-cyano-1,1,1-trifluoropropan-2-yl group or a 1-
cyanopropan-2-yl group, more preferably a 3-cyano-1,1,1-trifluoropropan-2-yl group.
As favorable compounds of the present invention for use as JAK inhibitors and as
preventive, therapeutic and/or improving agent for diseases against which inhibition of
JAK is effective, the following compounds may be mentioned.
30 (1) Compounds represented by the formula (I) wherein A1 is a cyclopentanediyl group
or a cyclohexanediyl group,
L1 is a methylene group or an ethylene group,
13
X1 is O, and
R1 is a C1-6 haloalkyl group, a cyano C1-6 haloalkyl group or a cyano C1-6 alkyl group,
tautomers or pharmaceutically acceptable salts of the compounds or solvates thereof.
(2) The compounds according to (1), wherein R1 is a 2,2,2-trifluoroethyl group, a
3,3,3-trifluoropropyl group, a 4,4,4-trifluorobutyl group, a 3,3-difluoropropyl group or a 5 2-
cyanoethyl group, tautomers or pharmaceutically acceptable salts of the compounds or
solvates thereof.
(3) Compounds represented by the formula (I) wherein A1 is a cyclopentanediyl group
or a cyclohexanediyl group,
10 L1 is a methylene group or an ethylene group,
X1 is NH, and
R1 is a cyano C1-6 haloalkyl group or a cyano C1-6 alkyl group, tautomers or
pharmaceutically acceptable salts of the compounds or solvates thereof.
(4) The compounds according to (3), wherein R1 is a 3-cyano-1,1,1-trifluoropropan-2-
15 yl group, a 4-cyano-1,1,1-trifluorobutan-2-yl group, a 3-cyano-1,1,1-trifluoropropan-2-yl
group, a 2-cyano-1,1,1-trifluoropropan-3-yl group, a 2-cyano-1,1,1-trifluoropropan-2-yl
group, a 2-cyanoethyl group or a 1-cyano-propan-2-yl group, tautomers or
pharmaceutically acceptable salts of the compounds or solvates thereof.
(5) The compounds according to any one of (1) to (4), wherein L1 is a methylene
20 group, tautomers or pharmaceutically acceptable salts of the compounds or solvates
thereof.
(6) The compounds according to any one of (1) to (5), wherein A1 is a
cyclohexanediyl group, tautomers or pharmaceutically acceptable salts of the
compounds or solvates thereof.
25 (7) Compounds represented by the formula (II) wherein A2 is a cyclopentanediyl
group or a cyclohexanediyl group,
L2 is a methylene group or an ethylene group, and
R2 is a 5 to 10-membered aromatic heterocyclic group (the heterocyclic group is
substituted with a halogen atom, a methyl group, an ethyl group, a trifluoromethyl group
30 or a 2,2,2-trifluoroethyl group), tautomers or pharmaceutically acceptable salts of the
compounds or solvates thereof.
(8) The compounds according to (7), wherein A2 is a cyclohexanediyl group,
14
tautomers or pharmaceutically acceptable salts of the compounds or solvates thereof.
(9) The compounds according to (7) or (8), wherein L2 is a methylene group,
tautomers or pharmaceutically acceptable salts of the compounds or solvates thereof.
(10) The compounds according to any one of (7) to (9), wherein R2 is a pyrrolyl group,
a thienyl group, a furyl group, a pyrazolyl group, an imidazolyl group, a thiazolyl group5 ,
an isothiazolyl group, an oxazolyl group, an isoxazolyl group, a 1H-1,2,4-triazolyl group,
a 4H-1,2,4- triazolyl group, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a
pyrazinyl group or a 1,3,5-triazinyl group (each of the pyrrolyl group to the 1,3,5-triazinyl
group is substituted with a fluorine atom, a chlorine atom, a bromine atom, a methyl
10 group or a trifluoromethyl group) , tautomers or pharmaceutically acceptable salts of the
compounds or solvates thereof.
(11) Compounds represented by the formula (III) wherein A3 is a cyclopentanediyl
group or a cyclohexanediyl group,
L3 is a methylene group or an ethylene group,
15 X3 is O, and
R3 is a C1-6 haloalkyl group, a cyano C1-6 haloalkyl group or a cyano C1-6 alkyl group,
tautomers or pharmaceutically acceptable salts of the compounds or solvates thereof.
(12) The compounds according to (11), wherein R3 is a 2,2,2-trifluoroethyl group, a
3,3,3-trifluoropropyl group, a 4,4,4-trifluorobutyl group, a 2,2-difluoroethyl group, a 3,3-
20 difluoropropyl group, a 3-cyano-1,1,1-trifluoropropan-2-yl group, a 2-cyano-1,1,1-
trifluoropropan-2-yl group, a 2-cyanoethyl group or a 1-cyanopropan-2-yl group,
tautomers or pharmaceutically acceptable salts of the compounds or solvates thereof.
(13) Compounds represented by the formula (III) wherein A3 is a cyclopentanediyl
group or a cyclohexanediyl group,
25 L3 is a methylene group or an ethylene group
X3 is NH, and
R3 is a cyano C1-6 haloalkyl group or a cyano C1-6 alkyl group, tautomers or
pharmaceutically acceptable salts of the compounds or solvates thereof.
(14) The compounds according to (13), wherein R3 is a 3-cyano-1,1,1-trifluoropropan-
30 2-yl group, a 2-cyano-1,1,1-trifluoropropan-2-yl group, a 2-cyanoethyl group or a 1-
cyanopropan-2-yl group, tautomers or pharmaceutically acceptable salts of the
compounds or solvates thereof.
15
(15) The compounds according to any one of (11) to (14), wherein A3 is a
cyclohexanediyl group, tautomers or pharmaceutically acceptable salts of the
compounds or solvates thereof.
(16) The compounds according to any one of (11) to (15), wherein L3 is a methylene
group, tautomers or pharmaceutically acceptable salts of the compounds or solvate5 s
thereof.
(17) Medicaments containing the compound as defined in any one of (1) to (16),
tautomers or pharmaceutically acceptable salts of the compounds or solvates thereof,
as an active ingredient.
10 In the present invention, the compounds of the present invention represented by
the formula (I), the formula (II) or the formula (III) may be present in the form of
tautomers or geometrical isomers which undergo endocyclic or exocyclic isomerization,
mixtures of tautomers or geometric isomers or mixtures of thereof. When the
compounds of the present invention have an asymmetric center, whether or not
15 resulting from an isomerization, the compounds of the present invention may be in the
form of resolved optical isomers or in the form of mixtures containing them in certain
ratios. Further, when the compounds of the present invention have two or more
asymmetric centers, the compounds of the present invention can be in the form of
diastereomers due to optical isomerism about them.
20 The compounds of the present invention may be in the form of a mixture of all
these isomers in certain ratios. For example, diastereomer can be separated by
techniques well known to those skilled in the art such as fractional crystallization, and
optical isomers can be obtained by techniques well known in the field of organic
chemistry for this purpose.
25 The present invention covers pharmaceutically acceptable salts of the compounds
of the present invention represented by the formula (I), the formula (II) or the formula
(III).
The compounds of the present invention represented by the formula (I), the
formula (II) or the formula (III) may be converted to pharmaceutically acceptable salts or
30 may be liberated from the resulting salts, if necessary.
The pharmaceutically acceptable salts of the present invention may be, for
example, salts with alkali metals (such as lithium, sodium and potassium), alkaline earth
16
metals (such as magnesium and calcium), ammonium, organic bases, amino acids,
inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid and
sulfuric acid) and organic acids (such as acetic acid, citric acid, maleic acid, fumaric
acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid and p-toluenesulfonic
acid)5 .
The compounds of the present invention represented by the formula (I), the
formula (II) or the formula (III) or pharmaceutically acceptable salts thereof may be in
the form of arbitrary crystals, depending on the production conditions. The present
invention covers these crystals.
10 The compounds of the present invention represented by the formula (I), the
formula (II) or the formula (III) or pharmaceutically acceptable salts thereof may be in
the form of arbitrary hydrates or solvates with organic solvents such as acetone, ethanol,
1-propanol and 2-propanol, and the present invention covers these hydrates, solvates
and their mixtures.
15 The present invention covers prodrugs of the compounds of the present invention
represented by the formula (I), the formula (II) or the formula (III).
Prodrugs are derivatives of medicinal compounds having chemically or
metabolically degradable groups and give pharmacologically active medicinal
compounds upon solvolysis or under physiological conditions in vivo. Methods for
20 selecting or producing appropriate prodrugs are disclosed in, for example, Design of
Prodrugs (Elsevier, Amsterdam 1985).
In the present invention, in the case of a compound having a hydroxy group,
prodrugs like acyloxy derivatives obtained by reacting the compound with appropriate
acyl halides, appropriate acid anhydrides or appropriate haloalkyloxycarbonyl
25 compounds may, for example, be mentioned. Structures particularly preferred as
prodrugs include –O-COC2H5, -O-CO(t-Bu), -O-COC15H31, -O-CO[m-(CO2Na)-C6H4],
-O-COCH2CH2CO2Na, -OCOCH(NH2)CH3, -O-COCH2N(CH3)2 or -O-CH2OCOCH3 or
the like.
In the case of a compound having an amino group, prodrugs obtained by reacting
30 the compound having an amino group with appropriate acid halides, appropriate mixed
acid anhydrides or haloalkyloxycarbonyl compounds may, for example, be mentioned.
Structures particularly preferred as prodrugs include -CO(CH2)20OCH3,
17
-COCH(NH2)CH3, -CH2OCOCH3 or the like.
The present invention is used when it is expected to improve pathology of
diseases associated with JAK1, JAK2 and JAK3 separately or in combination. Among
these diseases, rheumatoid arthritis is associated with JAK1. Among these diseases,
JAK1- and JAK3-associated diseases are, in addition to rheumatoid arthriti5 s,
inflammatory or proliferative dermatoses such as psoriasis, atopic dermatitis, contact
dermatitis, eczematoid dermatitis, seborrheic dermatitis, lichen planus, pemphigus,
pemphigoid, epidermolysis bullosa, hives, angioedema, angiitis, erythema, dermal
eosinophilia, lupus erythematosus, acne and alopecia areata, immune-mediated
10 dermatoses, reversible airway obstruction, mucitis and angitis.
In addition, asthma, Alzheimer disease, atherosclerosis, cancer, leukemia,
rejection of organ or tissue grafts (such as heart, kidney, liver, bone marrow, skin, horn,
lung, pancreas, islet, small intestine, extremities, muscles, nerves, intervertebral disks,
trachea, myoblasts and cartilage), graft-versus-host reaction after bone marrow
15 transplantation and autoimmune diseases such as rheumatic disease, systemic lupus
erythematosus (SLE), Hashimoto’s disease, multiple sclerosis, myasthenia gravis, type I
diabetes and diabetic complications are mentioned.
Among these diseases, JAK1- and JAK2-associated diseases are cancer,
leukemia, chronic myeloproliferative disorders and myelodysplastic syndrome.
20 As an application of the present invention, treatment, prevention or improvement
of the above-mentioned diseases may be mentioned, but there is no restriction.
The compounds of the present invention can be synthesized by the processes
mentioned later, but the production of the compounds of the present invention is not
restricted to these general examples.
25 The compounds of the present invention can usually be purified by column
chromatography, thin layer chromatography, high performance liquid chromatography
(HPLC) or high performance liquid chromatography-mass spectrometry (LC-MS) and, if
necessary, they may be obtained with high purity by recrystallization or washing with
solvents.
30 In general, in the production of the compounds of the present invention, any
solvents that are stable and inert under the reaction conditions and do not hinder the
reactions may be used without any particular restrictions, and for example, sulfoxide
18
solvents (such as dimethyl sulfoxide), amide solvents (such as N,N-dimethylformamide
or N,N-dimethylacetamide), ether solvents (such as ethyl ether, 1,2-dimethoxyethane,
tetrahydrofuran, 1,4-dioxane or cyclopentyl methyl ether), halogenated solvents (such
as dichloromethane, chloroform or 1,2-dichloroethane), nitrile solvents (such as
acetonitrile or propionitrile), aromatic hydrocarbon solvents (such as benzene o5 r
toluene), aliphatic hydrocarbon solvents (such as hexane or heptane), ester solvents
(such as ethyl acetate), alcohol solvents (such as methanol, ethanol, 1-propanol, 2-
propanol or ethylene glycol) and water may be mentioned. The reactions may be
carried out in an arbitrary mixture of solvents mentioned above or in the absence of a
10 solvent.
The production of the compounds of the present invention may be carried out at
ordinary pressure, under pressure, under reduced pressure or with microwave
irradiation.
In general, in the production of the compounds of the present invention, the
15 reaction temperature is chosen appropriately within the range of from -78 C to the
boiling point of the solvent used for the reaction.
As acids generally used in the production of the compounds of the present
invention, for example, organic acids (such as acetic acid, trifluoroacetic acid or ptoluenesulfonic
acid) and inorganic acids (such as sulfuric acid or hydrochloric acid)
20 may be mentioned.
As bases generally used in the production of the compounds of the present
invention, for example, organic metal compounds (such as n-butyllithium, s-butyllithium,
lithiumdiisopropylamide or isopropylmagnesium bromide), organic bases (such as
triethylamine, N,N-diisopropylethylamine or N,N-dimethylaminopyridine) or inorganic
25 bases (such as sodium carbonate, potassium carbonate, cesium carbonate, sodium
hydroxide, potassium hydroxide or sodium hydride) may be mentioned.
General processes for production of the compounds of the present invention are
shown below, and the formulae of the intermediate and the end product in each step
therein conceptually cover their protected derivatives, too.
30 Herein, protected derivatives are defined as compounds which can be converted
to the desired product, if necessary, through hydrolysis, reduction, oxidation, alkylation
or the like and include compounds protected with protective groups acceptable to
19
organic synthetic chemistry.
Protection and deprotection may be carried out by protection and deprotection
reactions using generally known protective groups (for example, by referring to
Protective Groups in Organic Synthesis, Fourth edition, T. W. Greene, John Wiley &
Sons Inc. (2006))5 .
Hydrolysis, reduction and oxidation may be carried out by generally known
functional group conversions (for example, by referring to Comprehensive Organic
Transformations, Second Edition, R.C.Larock, Wiley-VCH (1999)).
The compounds of the present invention represented by the formula (I), the
10 formula (II) and the formula (III) can be produced, for example, through the following
scheme (2) or (3).
According to the scheme (2), a compound (2)-2 can be obtained by treating a
compound (2)-1 with an equivalent or excessive amount of an unit (1)-3 in the presence
of a base such as N,N-diisopropylethylamine in an appropriate solvent or in the absence
15 of solvent at room temperature to a refluxing temperature.
A compound (2)-3 can be obtained by treating a compound (2)-2 with an
equivalent or excessive amount of 1,1’-carbonyldiimidazole in the presence of a base
such as N,N-diisopropylethylamine in an appropriate solvent or in the absence of
solvent at room temperature to a refluxing temperature.
20 According to the following scheme (3), a compound (3)-2 can be obtained by
treating a compound (3)-1 with an equivalent or excessive amount of a compound (4)-1
in an appropriate solvent at -78 C to a refluxing temperature.
A compound (3)-3 can be obtained by treating a compound (3)-2 with an
equivalent or excessive amount of a unit (1)-3 in the presence of a base such as
25 tripotassium phosphate in an appropriate solvent or in the absence of solvent at room
temperature to a refluxing temperature.
The unit (1)-3 used herein can be produced, for example, through the following
scheme (1).
According to the following scheme (1), a compound (1)-2 can be obtained by
30 treating a carboxylic acid (1) with an equivalent or excessive amount of
diphenylphosphoryl azide in the presence of a base such as triethylamine in an
appropriate solvent or in the absence of solvent at room temperature to a refluxing
20
temperature and then treating with an equivalent or excessive amount of benzyl alcohol
or tert-butyl alcohol and can be converted to a unit (1)-3 by an appropriate deprotection.
In the following schemes, Rpr is a hydrogen atom or a protective group such as a
Ts group, a TIPS group or a SEM group. When Rpr is not a hydrogen atom, it can be
converted to a hydrogen atom by an appropriate deprotection5 .
A is the same as A1, A2 or A3 previously defined, and may, for example, be a
cyclopropane-1,2-diyl group, a cyclobutane-1,3-diyl group, a cyclopentane-1,3-diyl
group, a cyclohexane-1,4-diyl group, a cycloheptane-1,4-diyl group or the like.
L is the same as L1, L2 or L3 previously defined, X is a single bond or the same as
10 X1 or X3 previously defined, and R is the same as R1, R2 or R3 previously defined.
Rb is a benzyl group, a t-butyl group or the like.
Q is a hydrogen atom or a protective group such as a TMS group. When Q is not
a hydrogen atom, it can be converted to a hydrogen atom by an appropriate
deprotection.
15 T is a group generating a carbanion at a terminal alkyne such as lithium or
magnesium bromide.
20 Now, the present invention will be described in further detail with reference to
Reference Synthetic Examples, Synthetic Examples, Pharmacological assay and
21
Formulation Examples. However, it should be understood that the present invention is
by no means restricted by these specific Examples.
In the Examples, “NMR” denotes nuclear magnetic resonance, “LC/MS” denotes
high performance liquid chromatography-mass spectrometry, “(v/v)” means
(volume/volume), “(v/v/v)” means (volume/volume/volume), “M” means mol/L. In th5 e
tables, “Rf” denotes Reference Synthetic Example, “Ex” denotes Synthetic Example,
“Data” denotes physical property data, “Yield” denotes yield of a synthesized
compound, “quant” denotes quantitative, and “min” denotes minute.
The 1H-NMR data show chemical shifts (unit: ppm) (splitting pattern, value of
10 integral) measured at 300 MHz (with JNM-ECP300, manufactured by JEOL Ltd or JNMECX300,
manufactured by JEOL Ltd) using tetramethylsilane as an internal standard,
“s” denotes “singlet”, “d” denotes “doublet”, “t” denotes “triplet”, “q” denotes “quartet”,
“quint” denotes quintet, “sextet” denotes sextet, “septet” denotes septet, “dd” denotes
doublet of doublets, “dt” denotes doublet of triplets, “td” denotes triplet of doublets, “dq”
15 denotes doublet of quartets, “qd” denotes quartet of doublets, “tt” denotes triplet of
triplets, “ddd” denotes doublet of doublet of doublets, “m” denotes multiplet, “br” denotes
broad, “J” denotes coupling constant, “CDCl3” denotes deuterated chloroform, “CD3OD”
denotes deuterated methanol, and “DMSO-d6” denotes deuterated dimethyl sulfoxide.
For purification by silica gel column chromatography, Hi-Flash (registered
20 trademark) column manufactured by Yamazen Corporation, a silica gel 60
manufactured by Merck KGaA, Darmstadt, Germany or PSQ60B manufactured by Fuji
Silysia Chemical Ltd. was used unless otherwise noted.
For purification by silica gel thin layer chromatography, PLC plate manufactured
by Merck KGaA, Darmstadt, Germany was used unless otherwise noted.
25 As a microwave reactor, Initiator sixty manufactured by Biotage was used.
The absolute configurations, if specified, are those of known compounds or those
of derivatives from known compounds, or those measured by single-crystal X-ray
structural analysis (with SMART APEX II ULTRA (manufactured by Bruker AXS), X ray:
CuK (50 kV, 24 mA), measurement temperature: -50 C).
30 LC/MS spectra were measured by using ESI (electrospray ionization). “ESI+”
denotes ESI-positive mode, and “ESI-“ denotes ESI-negative mode.
LC/MS measurement condition 1:
22
Instrument: Waters Alliance
Waters ZQ
Column: Waters SunFire C18 (3.5 m, 2.1×20 mm)
Column Temp.: 40 C
Eluents: Liquid A: 0.1 wt% aqueous formic aci5 d
Liquid B: 0.1 wt% formic acid in acetonitrile
Elution: A mixture of Liquids A and B was flown at 0.4 mL/min while the mixing
ratio was linearly changed from 90/10 (v/v) to 15/85 (v/v) over the first 3 minutes, and
then the flow rate was linearly changed to 0.5 mL/min over 2 minutes at a constant
10 mixing ratio of 15/85 (v/v). Then, the mixing ratio was linearly changed to 90/10 (v/v)
over 0.5 minute and maintained at 90/10 (v/v) for 2.5 minutes.
LC/MS measurement condition 2:
Instrument: Waters AQUITY UPLC-PDA/CAD
Thermo LTQ XL
15 Column: Waters AQUITY UPLC BEH C18 (1.7 m, 2.1×50 mm)
Column Temp.: 40 C
Eluents: Liquid A: 0.1 wt% aqueous formic acid
Liquid B: 0.1 wt% formic acid in acetonitrile
Elution: A mixture of Liquids A and B was flown at 0.6 mL/min at a mixing ratio
20 of 90/10 (v/v) for the first 0.5 minute, and then the mixing ratio was linearly changed to
10/90 (v/v) over 2.5 minutes and then maintained at 10/90 (v/v) for 0.7 minute. Then,
the mixing ratio and the flow rate were linearly changed to 90/10 (v/v) and 0.8 mL/min,
respectively, over 0.1 minute and maintained constant for 1 minute.
LC/MS measurement condition 3:
25 Instrument: Waters AQUITY UPLC-PDA/CAD
Thermo LTQ XL
Column: Waters AQUITY UPLC BEH C18 (1.7 m, 2.1×50 mm)
Column Temp.: 40 C
Eluents: Liquid A: 0.1 wt% aqueous formic acid
30 Liquid B: 0.1 wt% formic acid in acetonitrile
Elution: A mixture of Liquids A and B was flown at 0.6 mL/min while the mixing
ratio was linearly changed from 80/20 (v/v) to 0/100 (v/v) over 2.5 minutes, and the
23
mixing ratio was maintained at 0/100 (v/v) for 1.2 minutes. Then, the mixing ratio and
the flow rate were linearly changed to 80/20 (v/v) and 0.8 mL/min, respectively, over 0.1
minute and maintained constant for 1.0 minute.
LC/MS measurement condition 4:
Instrument: Waters AQUITY H-Class/PD5 A
Waters SQ Detector 2
Column: Waters AQUITY UPLC BEH C18 (1.7 m, 2.1×50 mm)
Column Temp.: 40 C
Eluents: Liquid A: 0.1 wt% aqueous formic acid
10 Liquid B: 0.1 wt% formic acid in acetonitrile
Elution: A mixture of Liquids A and B was flown at 0.6 mL/min while the mixing
ratio was linearly changed from 90/10 (v/v) to 10/90 (v/v) over 3 minutes, and then the
mixing ratio was maintained at 10/90 (v/v) for 0.7 minute. Then, the mixing ratio and
the flow rate were linearly changed to 90/10 (v/v) and 0.8 mL/min, respectively, over 0.1
15 minute and maintained constant for 1.0 minute.
REFERENCE SYNTHETIC EXAMPLE 1
Methyl trans-4-{[(benzyloxy)carbonyl]amino}cyclohexanecarboxylate
Commercially available trans-4-(methoxycarbonyl)cyclohexanecarboxylic acid
(15.7 g, 84.3 mmol) in toluene (160 mL) was stirred with triethylamine (35.0 mL, 253.0
20 mmol) at 110°C, and diphenylphosphoryl azide (20.0 mL, 92.7 mmol) was added
dropwise over 30 minutes. After 3 hours of stirring at 110°C, benzyl alcohol (11.3 ml,
109.6 mmol) was added dropwise over 10 minutes, and the reaction solution was stirred
for another 1 hour and 30 minutes. The reaction mixture was allowed to cool to room
temperature, and after addition of 10 wt% aqueous citric acid, extracted with ethyl
25 acetate. The organic layer was washed with saturated aqueous sodium hydrogen
carbonate and with saturated aqueous sodium chloride, dried over anhydrous sodium
sulfate and concentrated under reduced pressure. The residue was washed with a
solvent mixture of hexane/ethyl acetate (= 9/1 (v/v)) to give a mixture containing the title
compound as a white solid (18.0 g).
30 REFERENCE SYNTHETIC EXAMPLE 2
trans-4-{[(Benzyloxy)carbonyl]amino}cyclohexanecarboxylic acid
1 M aqueous sodium hydroxide (100 ml) was added to a solution of the mixture
24
(18.0 g) containing methyl trans-4-{[(benzyloxy)carbonyl]amino}cyclohexanecarboxylate
obtained in Reference Synthetic Example 1 in methanol (180 mL), and the resulting
reaction mixture was stirred for 1 day and acidified with concentrated hydrochloric acid.
The precipitated solid was washed with ethyl acetate and with water to give a mixture
containing the title compound as a white solid (13.0 g). Further, the filtrate wa5 s
extracted with ethyl acetate, and the organic layer was washed with saturated aqueous
ammonium chloride, dried over anhydrous sodium sulfate and concentrated under
reduced pressure to give a mixture containing the title compound as a white solid (6.7 g).
The white solids were combined and used for in the next step without further purification.
10 REFERENCE SYNTHETIC EXAMPLE 3
Benzyl [trans-4-(hydroxymethyl)cyclohexyl]carbamate
Boran - tetrahydrofuran complex (8.5 wt% in tetrahydrofuran, 30 mL) was added
dropwise to a solution of trans-4-{[(benzyloxy)carbonyl]amino}cyclohexanecarboxylic
acid (6.0 g) obtained in Reference Synthetic Example 2 in tetrahydrofuran (30 ml) under
15 cooling with ice, and the resulting reaction mixture was stirred at room temperature for 1
day, and after addition of acetic acid, extracted with ethyl acetate. The organic layer
was washed with saturated aqueous sodium hydrogen carbonate and with saturated
aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under
reduced pressure. The resulting solid was washed with a solvent mixture of
20 hexane/ethyl acetate (= 10/1 (v/v)) to give a mixture containing the title compound as a
white solid (6.0 g).
REFERENCE SYNTHETIC EXAMPLE 4
Benzyl {trans-4-[(3,3,3-trifluoropropoxy)methyl]cyclohexyl}carbamate
A solution of benzyl [trans-4-(hydroxymethyl)cyclohexyl]carbamate (630 mg, 2.39
25 mmol) obtained in Reference Synthetic Example 3 in dichloromethane (5 mL) was
stirred with 1,1,1-trifluoro-3-iodopropane (250 L, 2.20 mmol), 2,6-di-tert-butylpyridine
(500 L, 2.27 mmol) and silver trifluoromethanesulfonate (500 mg, 1.99 mmol) for 5
hours and with 1,1,1-trifluoro-3-iodopropane (100 L, 0.880 mmol), 2,6-di-tertbutylpyridine
(200 L, 0.909 mmol) and silver trifluoromethanesulfonate (200 mg, 0.797
30 mmol) for 1 day. After addition of saturated aqueous ammonium chloride, the reaction
mixture was extracted with ethyl acetate. The organic layer was washed with
saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate
25
and concentrated under reduced pressure. The residue was purified by silica gel
column chromatography (hexane/ethyl acetate = 10/1 3/1 (v/v)) to give a mixture
containing the title compound as a white amorphous (478 mg).
REFERENCE SYNTHETIC EXAMPLE 5
trans-4-[(3,3,3-Trifluoropropoxy)methyl]cyclohexanamin5 e
A solution of the mixture (478 mg) containing benzyl {trans-4-[(3,3,3-
trifluoropropoxy)methyl]cyclohexyl}carbamate obtained in Reference Synthetic Example
4 in methanol (5 mL) was stirred with 10 wt% palladium-carbon (50 wt% aq., 200 mg)
under a hydrogen atmosphere for 2 hours and then filtered. The filter cake was
10 washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to
give a mixture containing the title compound as a gray amorphous (308 mg).
REFERENCE SYNTHETIC EXAMPLE 6
1-{trans-4-[(Benzylamino)methyl]cyclohexyl}-7-{[2-(trimethylsilyl)ethoxy]methyl}-1Hpyrrolo[
3’,2’:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione
15 A mixture of trans-4-(2,4-dioxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-2,3,4,7-
tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-1-yl)cyclohexanecarbaldehyde
(300 mg, 0.678 mmol) obtained in accordance with Reference Synthetic Exampleb 168
in WO2013/024895, methanol (10 mL) and acetic acid (1 mL) was stirred with
benzylamine (141 L, 2.03 mmol) at room temperature for 1 hour and then stirred with
20 2-picoline borane (109 mg, 1.02 mmol) at room temperature for 1 day. After addition of
water, the reaction solution was extracted with chloroform, and the organic layer was
washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate
and concentrated under reduced pressure. The resulting residue was purified by silica
gel column chromatography (chloroform/methanol = 100/1 (v/v)) to give the title
25 compound as a white solid (274 mg, yield 76%).
REFERENCE SYNTHETIC EXAMPLE 7
1-[trans-4-(Aminomethyl)cyclohexyl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1Hpyrrolo[
3’,2’:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione acetate
A mixture of 1-{trans-4-[(benzylamino)methyl]cyclohexyl}-7-{[2-
30 (trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-
dione (270 mg, 0.506 mmol) obtained in Reference Synthetic Example 6, 5 wt%
palladium-carbon (50 wt% aq., 27 mg), methanol (3 mL), tetrahydrofuran (3 mL) and
26
acetic acid (0.1 mL) was stirred under a hydrogen atmosphere at room temperature for
1 day. The reaction mixture was filtered, and the filtrate was concentrated under
reduced pressure. The residue was washed with acetic acid and hexane to give the
title compound as a white solid (232 mg, yield 90%).
REFERENCE SYNTHETIC EXAMPLE 5 8
3-({[trans-4-(2,4-Dioxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-2,3,4,7-tetrahydro-1Hpyrrolo[
3’,2’:5,6]pyrido[4,3-d]pyrimidin-1-yl)cyclohexyl]methyl}amino)-4,4,4-
trifluorobutanenitrile
A solution of 1-[trans-4-(aminomethyl)cyclohexyl]-7-{[2-
10 (trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-
dione acetate (52.5 mg, 0.1 mmol) obtained in Reference Synthetic Example 7 in
acetonitrile (1.2 mL) was stirred with 1,8-diazabicyclo[5.4.0]undec-7-ene (15.6 L, 1.0
mmol) and 4,4,4-trifluorocrotononitrile (50.0 mg, 0.5 mmol) at room temperature for 3
days. After addition of water, the reaction mixture was extracted with ethyl acetate.
15 The organic layer was washed with saturated aqueous sodium chloride, dried over
anhydrous sodium sulfate and concentrated under reduced pressure. The resulting
residue was purified by silica gel column chromatography (HiFlash (registered
trademark) column amino type manufactured by Yamazen Corporation: hexane/ethyl
acetate = 2/1 (v/v) ethyl acetate ethyl acetate/methanol = 10/1 (v/v)) to give the title
20 compound as a light brown solid (25.2 mg, yield 43%).
REFERENCE SYNTHETIC EXAMPLE 9
(R)-3-({[trans-4-(2,4-Dioxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-2,3,4,7-tetrahydro-1Hpyrrolo[
3’,2’:5,6]pyrido[4,3-d]pyrimidin-1-yl)cyclohexyl]methyl}amino)-4,4,4-
trifluorobutanenitrile
25 3-({[trans-4-(2,4-Dioxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-2,3,4,7-tetrahydro-1Hpyrrolo[
3’,2’:5,6]pyrido[4,3-d]pyrimidin-1-yl)cyclohexyl]methyl}amino)-4,4,4-
trifluorobutanenitrile (126.8 mg, 0.2 mmol) obtained in Reference Synthetic Example 8
was purified by silica gel column chromatography (chiral column for medium pressure;
CHIRALFLASH (registered trademark) IA: hexane/ethanol = 9/1 7/3 (v/v)), and the
30 fraction eluted at a retention time of 49-58 minutes was concentrated to give the title
compound as a light brown solid (35.4 mg, yield 28%).
REFERENCE SYNTHETIC EXAMPLE 10
27
[trans-4-(2,4-Dioxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-2,3,4,7-tetrahydro-1Hpyrrolo[
3’,2’:5,6]pyrido[4,3-d]pyrimidin-1-yl)cyclohexyl]methyl 1H-imidazole-1-
carboxylate
A solution of 4-{[trans-4-(hydroxymethyl)cyclohexyl]amino}-1-{[2-
(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (6.03 g, 14.5 4
mmol) obtained in accordance with Reference Synthetic Exampleb 166 in
WO2013/024895 and 1,1’-carbonyldiimidazole (11.7 g, 72.0 mmol) in N,Ndimethylacetamide
(30 mL) was stirred with N,N-diisopropylethylamine (30 mL) at
120°C for 2 hours and 20 minutes. The reaction solution was allowed to cool to room
10 temperature and extracted by adding ethyl acetate (150 mL), saturated aqueous
ammonium chloride (30 mL) and water, and the aqueous layer was extracted with ethyl
acetate. The resulting organic layers were combined, washed with saturated aqueous
ammonium chloride three times and then with saturated aqueous sodium chloride, dried
over anhydrous sodium sulfate and concentrated under reduced pressure. The
15 residue was filtered, and the collected solid was washed with hexane and dried under
reduced pressure to give the title compound as a pale yellow solid (7.56 g, yield 97%).
REFERENCE SYNTHETIC EXAMPLE 11
1-[trans-4-(Hydroxymethyl)cyclohexyl]-3,7-bis{[2-(trimethylsilyl)ethoxy]methyl}-1Hpyrrolo[
3’,2’:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione
20 A solution of [trans-4-(2,4-dioxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-2,3,4,7-
tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-1-yl)cyclohexyl]methyl 1Himidazole-
1-carboxylate (7.56 g, 14.0 mmol) obtained in Reference Synthetic Example
10 in N,N-dimethylformamide(140 mL) was cooled to 0°C and stirred with sodium
hydride (55 wt% dispersion in mineral oil, 760 mg, 18.2 mmol) and [2-
25 (chloromethoxy)ethyl]trimethylsilane (3.50 mL, 19.6 mmol) for 2 hours. After addition
of water and saturated aqueous ammonium chloride, the reaction mixture was extracted
with ethyl acetate. The organic layer was washed with saturated aqueous sodium
chloride, dried over anhydrous sodium sulfate and concentrated under reduced
pressure. The resulting residue was stirred with 1,4-dioxane (100 mL) and 1 M
30 aqueous sodium hydroxide (30 mL) at room temperature for 2 hours. After addition of
saturated aqueous ammonium chloride, the reaction mixture was extracted with ethyl
acetate. The organic layer was washed with saturated aqueous sodium chloride, dried
28
over anhydrous sodium sulfate and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (hexane/ethyl acetate = 70/30
47/53 (v/v)) to give the title compound as a yellow amorphous (5.87 g, yield 73%).
REFERENCE SYNTHETIC EXAMPLE 12
1-{trans-4-[(3,3,3-Trifluoropropoxy)methyl]cyclohexyl}-3,7-bis{[5 2-
(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-
dione
A solution of 1-[trans-4-(hydroxymethyl)cyclohexyl]-3,7-bis{[2-
(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-
10 dione (1.35 g, 2.35 mmol) obtained in Reference Synthetic Example 11 in
dichloromethane (14 mL) was stirred with 1,1,1-trifluoro-3-iodopropane (1.34 mL, 11.8
mmol), 2,6-di-tert-butylpyridine (2.38 mL, 10.8 mmol) and silver
trifluoromethanesulfonate (2.60 g, 10.1 mmol) for 113 hours. The reaction mixture was
filtered, and the filtrate was extracted by adding chloroform and water. The resulting
15 organic layer was dried over anhydrous sodium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column chromatography three times
(the first run: hexane/ethyl acetate = 1/0 78/22 (v/v), the second run: hexane/ethyl
acetate = 1/0 4/1 (v/v), the third run: hexane/ethyl acetate = 1/0 4/1 (v/v)) to give
the title compound as a colorless amorphous (1.34 g, yield 85%).
20 REFERENCE SYNTHETIC EXAMPLE 13
4-Chloro-N-methoxy-N-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-
b]pyridine-5-carboxamide
A solution of 4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-
5-carboxylic acid (27.7 g, 84.8 mmol) obtained in accordance with Reference Synthetic
25 Exampleb 87 in WO2013/024895 in dichloromethane (280 mL) was stirred with N,Ndiisopropylethylamine
(43.2 mL, 254 mmol) and N-hydroxybenzotriazole (4.58 g, 33.9
mmol) for 15 minutes and then stirred with N,-dimethylhydroxylamine hydrochloride
(24.8 g, 254 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(48.7 g, 254 mmol) at room temperature for 18 hours. After addition of water, the
30 reaction mixture was extracted with chloroform twice. The organic layer was washed
with saturated aqueous ammonium chloride, saturated aqueous sodium hydrogen
carbonate and saturated aqueous sodium chloride, successively, dried over anhydrous
29
sodium sulfate and concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (hexane/ethyl acetate = 4/1 3/1 (v/v)) to give the
title compound as a yellow oil (30.5 g, yield 97%).
REFERENCE SYNTHETIC EXAMPLE 14
1-(4-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)prop-2-yn-5 1-
one
A solution of 4-chloro-N-methoxy-N-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1Hpyrrolo[
2,3-b]pyridine-5-carboxamide (47.4 g, 128 mmol) obtained in Reference
Synthetic Example 13 in tetrahydrofuran (150 mL) was stirred at 50-53°C, and after
10 addition of ethynylmagnesium bromide (0.5 M tetrahydrofuran solution, 310 mL, 153
mmol) at a temperature of 46°C or above, the reaction mixture was stirred for 3 hours,
cooled by air to 30°C and poured into ice -1 M hydrochloric acid (300 g-300 mL). The
resulting mixture was stirred for 15 minutes and extracted with ethyl acetate. The
resulting organic layer was washed with saturated aqueous sodium hydrogen carbonate
15 and with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The residue was filtered, and the collected
solid was washed with hexane and dried under reduced pressure to give the title
compound as a light brown solid (35.4 g, yield 83%).
REFERENCE SYNTHETIC EXAMPLE 15
20 1-[trans-4-(Hydroxymethyl)cyclohexyl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1Hpyrrolo[
2,3-h][1,6]naphthyridin-4(7H)-one
To 1-(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-
yl)prop-2-yn-1-one (35.3 g, 105 mmol) obtained in Reference Synthetic Example 14,
(trans-4-aminocyclohexyl)methanol (16.4 g, 126 mmol) obtained in accordance with
25 Reference Synthetic Exampleb 122 in WO2013/024895, tripotassium phosphate (44.7 g,
210 mmol) and dimethyl sulfoxide (175 mL) were added, and the reaction mixture was
stirred at 100-110°C for 2 hour and 30 minutes and allowed to cool to 50°C. Water
was added to the reaction mixture, and the resulting solid was collected by filtration,
washed with ethyl acetate and dried under reduced pressure to give the title compound
30 as a pale yellow solid (32.1 g, yield 71%).
REFERENCE SYNTHETIC EXAMPLE 16
Mixture of 1-(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-
30
yl)pyop-2-yn-1-one and 1-(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-
b]pyridin-5-yl)-3-[methoxy(methyl)amino]prop-2-en-1-one
Ethylmagnesium bromide (0.5 M tetrahydrofuran solution, 180 mL, 90.1 mmol)
was stirred with a solution of 4-chloro-N-methoxy-N-methyl-1-{[2-
(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (27.8 g, 75.5 1
mmol) obtained in Reference Synthetic Example 13 in tetrahydrofuran (84.0 mL) at
room temperature for 30 minutes, then heated to 50°C and stirred for another 1 hour.
The reaction mixture was cooled with ice, and after addition of saturated aqueous
ammonium chloride, extracted with ethyl acetate. The organic layer was washed with
10 saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The residue was dried at 50°C under reduced
pressure for 1 hour to give a brown oil containing the title compound (29.7 g). The
brown oil was used for the next step without further purification.
REFERENCE SYNTHETIC EXAMPLE 17
15 1-[trans-4-(Hydroxymethyl)cyclohexyl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1Hpyrrolo[
2,3-h][1,6]naphthyridin-4(7H)-one
A solution of the mixture (29.7 g) of 1-(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-
1H-pyrrolo[2,3-b]pyridin-5-yl)prop-2-yn-1-one and 1-(4-chloro-1-{[2-
(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-
20 [methoxy(methyl)amino]prop-2-en-1-one obtained in Reference Synthetic Example 16 in
dimethyl sulfoxide (300 mL) was stirred with tripotassium phosphate (31.9 g, 150 mmol)
and (trans-4-aminocyclohexyl)methanol (11.6 g, 90.1 mmol) obtained in accordance
with Reference Synthetic Exampleb 122 in WO2013/024895 at 90°C for 3 hours and
then at 110°C for another 4 hours. The reaction mixture was allowed to cool to room
25 temperature, and water and hexane were added. The precipitated solid was collected
by filtration, washed with water, a solvent mixture of hexane/ethyl acetate (= 1/1 (v/v))
and ethyl acetate successively and dried at 50°C for 5 hours under reduced pressure to
give the title compound as a light brown solid (24.1 g, yield 75%). (Alternative to
Reference Synthetic Example 15)
30 REFERENCE SYNTHETIC EXAMPLE 18
trans-4-(4-Oxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydro-1H-pyrrolo[2,3-
h][1,6]naphthyridin-1-yl)cyclohexanecarbaldehyde
31
A mixture of 1-[trans-4-(hydroxymethyl)cyclohexyl]-7-{[2-
(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one (1.07 g, 2.49
mmol) obtained in Reference Synthetic Example 15, dimethyl sulfoxide (21 mL) and
dichloromethane (21 mL) was stirred with 2-iodoxybenzoic acid (1.05 g, 3.74 mmol) at
40°C for 1 hour and 30 minutes. After addition of saturated aqueous sodiu5 m
thiosulfate and saturated aqueous sodium hydrogen carbonate, the reaction mixture
was extracted with ethyl acetate. The resulting organic layer was washed with
saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The residue was purified by silica gel column
10 chromatography (ethyl acetate ethyl acetate/methanol = 10/1 (v/v)) to give the title
compound as a grey solid (827 mg, yield 78%).
REFERENCE SYNTHETIC EXAMPLE 19
1-{trans-4-[(Benzylamino)methyl]cyclohexyl}-7-{[2-(trimethylsilyl)ethoxy]methyl}-1Hpyrrolo[
2,3-h][1,6]naphthyridin-4(7H)-one
15 Benzylamine (384 L, 3.52 mmol) and 2-picoline borane (188 mg, 1.78 mmol)
were added to a mixture of trans-4-(4-oxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-
dihydro-1H-pyrrolo[2,3-h][1,6]naphthyridin-1-yl)cyclohexanecarbaldehyde (500 mg, 1.17
mmol) obtained in Reference Synthetic Example 18, methanol (10 mL) and acetic acid
(1.0 mL), and the resulting reaction mixture was stirred at room temperature for 1 day,
20 and after addition of 1 M hydrochloric acid, extracted with ethyl acetate. The aqueous
layer was mixed with 1 M aqueous sodium hydroxide and extracted with a solvent
mixture of chloroform/2-propanol (= 1/1 (v/v)). The organic layer was dried over
anhydrous sodium sulfate and concentrated under reduced pressure. The resulting
residue was purified by silica gel column chromatography (HiFlash (registered
25 trademark) column amino type manufactured by Yamazen Corporation: hexane/ethyl
acetate = 1/1 (v/v) ethyl acetate ethyl acetate/methanol = 10/1 (v/v)) to give the
title compound as a pale yellow oil (390 mg, yield 65%).
REFERENCE SYNTHETIC EXAMPLE 20
1-[trans-4-(Aminomethyl)cyclohexyl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-
30 h][1,6]naphthyridin-4(7H)-one
A mixture of 1-{trans-4-[(benzylamino)methyl]cyclohexyl}-7-{[2-
(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one (390 mg,
32
0.755 mmol) obtained in Reference Synthetic Example 19, methanol (5 mL),
tetrahydrofuran (5 mL) and acetic acid (1 mL) was stirred with 10 wt% palladium-carbon
(50 wt% aq., 59.0 mg) under a hydrogen atmosphere for 1 day and then filtered. The
filter cake was washed with ethyl acetate, and the filtrate was concentrated under
reduced pressure. The residue was purified by silica gel column chromatograph5 y
(HiFlash (registered trademark) column amino type manufactured by Yamazen
Corporation: ethyl acetate/methanol = 10/1 chloroform/methanol = 10/1 (v/v)) to give
the title compound as a white solid (271 mg, yield 84%).
REFERENCE SYNTHETIC EXAMPLE 21
10 4,4,4-Trifluoro-3-({[trans-4-(4-oxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydro-1Hpyrrolo[
2,3-h][1,6]naphthyridin-1-yl)cyclohexyl]methyl}amino)butanenitrile
The reactions in Reference Synthetic Example 8 were carried out in substantially
the same manners except that 1-[trans-4-(aminomethyl)cyclohexyl]-7-{[2-
(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one (50.0 mg,
15 0.117 mmol) obtained in Reference Synthetic Example 20 was used instead of 1-[trans-
4-(aminomethyl)cyclohexyl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1Hpyrrolo[
3’,2’:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione acetate obtained in Reference
Synthetic Example 7 to give the title compound as a brown oil (54.5 mg, yield 85%).
REFERENCE SYNTHETIC EXAMPLE 22
20 (R)-4,4,4-Trifluoro-3-({[trans-4-(4-oxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydro-
1H-pyrrolo[2,3-h][1,6]naphthyridin-1-yl)cyclohexyl]methyl}amino)butanenitrile
4,4,4-Trifluoro-3-({[trans-4-(4-oxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydro-
1H-pyrrolo[2,3-h][1,6]naphthyridin-1-yl)cyclohexyl]methyl}amino)butanenitrile (129 mg,
0.236 mmol) obtained in Reference Synthetic Example 21 was purified by preparative
25 high performance liquid chromatography (CHIRALPAK (registered trademark) IE 5 m
20×250 mm: hexane/ethanol/diethylamine = 70/30/0.1 (v/v/v): flow rate 8 mL/min),
and the fraction eluted at a retention time of 74.64 minutes containing a single optical
isomer was concentrated to give the title compound as a light brown oil (53.9 mg, yield
42%).
30 REFERENCE SYNTHETIC EXAMPLE 23
[trans-4-(4-Oxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydro-1H-pyrrolo[2,3-
h][1,6]naphthyridin-1-yl)cyclohexyl]methyl methanesulfonate
33
To a solution of 1-[trans-4-(hydroxymethyl)cyclohexyl]-7-{[2-
(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one (1.50 g, 3.51
mmol) obtained in Reference Synthetic Example 15 in dichloromethane (35 mL) cooled
to 0°C, triethylamine (1.47 mL, 10.5 mmol) was added, and then methanesulfonyl
chloride (326 L, 4.21 mmol) was gradually added dropwise. The reaction mixture wa5 s
warmed to room temperature and stirred for 1 hour, cooled with ice, then mixed with
water and extracted with ethyl acetate. The resulting organic layer was washed with
saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The residue was purified by silica gel column
10 chromatography (ethyl acetate ethyl acetate/methanol = 10/1 (v/v)) to give the title
compound as a yellow amorphous (1.53 g, yield 86%).
REFERENCE SYNTHETIC EXAMPLE 24
1-{trans-4-[(4-Methyl-1H-pyrazol-1-yl)methyl]cyclohexyl}-7-{[2-
(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one
15 To a solution of [trans-4-(4-oxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydro-1Hpyrrolo[
2,3-h][1,6]naphthyridin-1-yl)cyclohexyl]methyl methanesulfonate (1.53 g, 3.03
mmol) obtained in Reference Synthetic Example 23 in N,N-dimethylformamide (30 mL)
cooled to 0°C, 4-methyl-1H-pyrazole (500 L, 6.06 mmol) was added, and then sodium
hydride (55 wt% dispersion in mineral oil, 264 mg, 6.06 mmol) was gradually added.
20 Then, the reaction mixture was warmed to room temperature, stirred for 12 hours, and
after addition of water under cooling with ice, extracted with ethyl acetate. The
resulting organic layer was washed with saturated aqueous sodium chloride, dried over
anhydrous sodium sulfate and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (ethyl acetate ethyl acetate/methanol =
25 10/1 (v/v)) to give the title compound as a colorless amorphous (1.33 g, yield 89%).
REFERENCE SYNTHETIC EXAMPLE 25
1-{trans-4-[(2,2,2-Trifluoroethoxy)methyl]cyclohexyl}-7-{[2-(trimethylsilyl)ethoxy]methyl}-
1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one
To a solution of 1-[trans-4-(hydroxymethyl)cyclohexyl]-7-{[2-
30 (trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one (20 mg,
0.047 mmol) obtained in Reference Synthetic Example 15 in tetrahydrofuran (2 mL),
2,2,2-trifluoroethyl trifluoromethanesulfonate (50 L, 0.35 mmol) and sodium hydride
34
(55 wt% dispersion in mineral oil, 10 mg, 0.23 mmol) were added, and the reaction
mixture was stirred at room temperature for 2 hours. Then, 2,2,2-trifluoroethyl
trifluoromethanesulfonate (50 L, 0.35 mmol) and sodium hydride (55 wt% dispersion in
mineral oil, 10 mg, 0.23 mmol) were added, and the reaction mixture was stirred at
room temperature for another 2 hours. After addition of saturated aqueous sodiu5 m
chloride, the reaction mixture was extracted with ethyl acetate. The resulting organic
layer was dried over anhydrous sodium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column chromatography (hexane/ethyl
acetate = 5/1 0/1 ethyl acetate/methanol = 5/1 (v/v)) to give a mixture containing
10 the title compound as a colorless oil (9.2 mg). The mixture containing the title
compound was used for the next step without further purification.
REFERENCE SYNTHETIC EXAMPLE 26
1-{trans-4-[(3,3,3-Trifluoropropoxy)methyl]cyclohexyl}-7-{[2-
(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one
15 A solution of 1-(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-
b]pyridin-5-yl)prop-2-yn-1-one (279 mg, 0.83 mmol) obtained in Reference Synthetic
Example 14 in dimethyl sulfoxide (175 mL) was stirred with trans-4-[(3,3,3-
trifluoropropoxy)methyl]cyclohexanamine (255 mg, 1.00 mmol) obtained in Reference
Synthetic Example 5 and tripotassium phosphate (528 mg, 2.49 mmol) at 100°C for 1
20 hour and then with trans-4-[(3,3,3-trifluoropropoxy)methyl]cyclohexanamine (51 mg, 0.2
mmol) at 100°C for 2 hours. After addition water, the reaction mixture was extracted
with ethyl acetate. The resulting organic layer was dried over anhydrous sodium
sulfate and concentrated under reduced pressure. The resulting reddish oil (550 mg)
containing the title compound was dissolved in methanol (5.5 mL) and stirred with 5
25 wt% palladium-carbon (50 wt% aq., 100 mg) under a hydrogen atmosphere at room
temperature for 22 hours. The reaction mixture was filtered, and the filtrate was
concentrated under reduced pressure. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate = 2/1 1/1 0/1 (v/v)) to give the title
compound as a pale yellow oil (323 mg, yield 74%).
30 REFERENCE SYNTHETIC EXAMPLE 27
4,4,4-Trifluoro-3-{[trans-4-(4-oxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydro-1Hpyrrolo[
2,3-h][1,6]naphthyridin-1-yl)cyclohexyl]methoxy}butanenitrile
35
A solution of 1-[trans-4-(hydroxymethyl)cyclohexyl]-7-{[2-
(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one (14.5 g, 33.9
mmol) obtained in Reference Synthetic Example 15 in dichloromethane (290 mL) was
stirred with 1,8-diazabicyclo[5.4.0]undec-7-ene (20.3 mL, 135 mmol) at 40°C for 1 hour.
The reaction mixture was cooled to room temperature and stirred with 4,4,45 -
trifluorocrotononitrile (7.13 mL, 67.7 mmol) at 30°C for another 5 hours. After addition
of ethyl acetate, the reaction mixture was concentrated under reduced pressure, and
after addition of 10 wt% aqueous citric acid, extracted with ethyl acetate. The resulting
organic layer was washed with saturated aqueous ammonium chloride and saturated
10 aqueous sodium chloride successively, dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The residue was purified by silica gel column
chromatography (HiFlash (registered trademark) column manufactured by Yamazen
Corporation: ethyl acetate/hexane = 1/1 2/1 1/0 (v/v), then ethyl acetate/methanol
= 35/1 (v/v)) twice. The resulting solid was further purified by silica gel column
15 chromatography (PSQ60B manufactured by Fuji Silysia Chemical Ltd.: ethyl
acetate/hexane = 1/1 2/1 1/0 (v/v)) to give the title compound as a yellow solid
(15.7 g, yield 85%).
REFERENCE SYNTHETIC EXAMPLE 28
Mixture of 1-(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-
20 3-(trimethylsilyl)pyop-2-yn-1-one and 1-(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1Hpyrrolo[
2,3-b]pyridin-5-yl)prop-2-yn-1-one
n-Butyllithium (1.5 M normal hexane solution, 1.1 mL, 1.67 mmol) was added
dropwise to a solution of trimethylsilylacetylene (0.26 mL, 1.83 mmol) in tetrahydrofuran
(2.8 mL) at -15°C, and the reaction solution was stirred for 15 minutes. Then, a
25 solution of 4-chloro-N-methoxy-N-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1Hpyrrolo[
2,3-b]pyridine-5-carboxamide (564 mg, 1.52 mmol) obtained in Reference
Synthetic Example 13 in tetrahydrofuran (2.8 mL) was added at -15°C, and the reaction
solution was stirred at 0°C for 30 minutes, poured into a mixture of ice- 1 M hydrochloric
acid (10 g - 10 mL), then stirred for 15 minutes and extracted with ethyl acetate. The
30 resulting organic layer was dried over anhydrous sodium sulfate and concentrated
under reduced pressure to give a mixture containing the title compounds as yellow oil
(572 mg). The mixture containing the title compounds was used for the next step
36
without further purification.
REFERENCE SYNTHETIC EXAMPLE 29
1-[trans-4-(Hydroxymethyl)cyclohexyl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1Hpyrrolo[
2,3-h][1,6]naphthyridin-4(7H)-one
A solution of the mixture (572 mg) of 1-(4-chloro-1-{[5 2-
(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(trimethylsilyl)prop-2-yn-1-
one and 1-(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-
yl)pyop-2-yn-1-one obtained in Reference Synthetic Example 28 in dimethyl sulfoxide (5
mL) was stirred with tripotassium phosphate (645 mg, 3.04 mmol) and (trans-4-
10 aminocyclohexyl)methanol (237 mg, 1.82 mmol) obtained in accordance with Reference
Synthetic Exampleb 122 in WO2013/024895 at 110°C for 3 hours, and after addition of
water, stirred at 50°C for 2 hours. The precipitated solid was collected by filtration,
washed with water and ethyl acetate successively and dried at 50°C for 5 hours under
reduced pressure to give the title compound as a pale yellow solid (340 mg, yield 52%).
15 Separately, the washings were concentrated under reduced pressure, and the resulting
brown solid was washed with ethyl acetate and dried at 50°C for 3 hours to give the title
compound as a pale yellow solid (68 mg, yield 10%). (Alternative to Reference
Synthetic Example 15)
SYNTHETIC EXAMPLE 1
20 (R)-3-({[trans-4-(2,4-Dioxo-2,3,4,7-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-
1-yl)cyclohexyl]methyl}amino)-4,4,4-trifluorobutanenitrile
A solution of (R)-3-({[trans-4-(2,4-dioxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-2,3,4,7-
tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-1-yl)cyclohexyl]methyl}amino)-
4,4,4-trifluorobutanenitrile (662 mg, 1.2 mmol) obtained in Reference Synthetic Example
25 9 in dichloromethane (13 mL) was stirred with trifluoroacetic acid (1.3 mL) at room
temperature for 1 day and then stirred with trifluoroacetic acid (0.7 mL) at room
temperature for another 3 hours. The reaction mixture was concentrated under
reduced pressure to give a pale yellow oil containing (R)-4,4,4-trifluoro-3-[({trans-4-[7-
(hydroxymethyl)-2,4-dioxo-2,3,4,7-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-
30 1-yl]cyclohexyl}methyl)amino]butanenitrile as an intermediate (LC/MS: measurement
condition 2, retention time = 1.88 min, LC/MS(ESI+) m/z; 465 [M+H]+). The
intermediate was stirred with methanol (13 mL) and ethylenediamine (1.3 mL) at room
37
temperature for 1 day. After addition of water and methanol, the reaction mixture was
filtered. The collected solid was washed with methanol and dried under reduced
pressure to give the title compound as a colorless solid (405 mg, yield 80%).
SYNTHETIC EXAMPLE 2
1-{trans-4-[(3,3,3-Trifluoropropoxy)methyl]cyclohexyl}-1H-pyrrolo[3’,2’:5,6]pyrido[4,35 -
d]pyrimidine-2,4(3H,7H)-dione
The reactions in Synthetic Example 1 were carried out in substantially the same
manners except that 1-{trans-4-[(3,3,3-trifluoropropoxy)methyl]cyclohexyl}-3,7-bis{[2-
(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-
10 dione (790 mg, 1.18 mmol) obtained in Reference Synthetic Example 12 was used
instead of (R)-3-({[trans-4-(2,4-dioxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-2,3,4,7-
tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidin-1-yl)cyclohexyl]methyl}amino)-
4,4,4-trifluorobutanenitrile obtained in Reference Synthetic Example 9, and that 3,7-bis
(hydroxymethyl)-1-{trans-4-[(3,3,3-trifluoropropoxy)methyl]cyclohexyl}-1H15
pyrrolo[3’,2’:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione (LC/MS: measurement
condition 3, retention time = 1.31 min, LC/MS(ESI+) m/z; 471 [M+H]+) was obtained as
an intermediate, and the reaction mixture was filtered. The collected solid was washed
with ethyl acetate to give the title compound as a white solid (416 mg, yield 86%).
SYNTHETIC EXAMPLE 3
20 (R)-4,4,4-Trifluoro-3-({[trans-4-(4-oxo-4,7-dihydro-1H-pyrrolo[2,3-h][1,6]naphthyridin-1-
yl)cyclohexyl]methyl}amino)butanenitrile
The reactions in Synthetic Example 1 were carried out in substantially the same
manners except that (R)-4,4,4-trifluoro-3-({[trans-4-(4-oxo-7-{[2-
(trimethylsilyl)ethoxy]methyl}-4,7-dihydro-1H-pyrrolo[2,3-h][1,6]naphthyridin-1-
25 yl)cyclohexyl]methyl}amino)butanenitrile (1.11 g, 1.85 mmol) obtained in Reference
Synthetic Example 22 was used instead of (R)-3-({[trans-4-(2,4-dioxo-7-{[2-
(trimethylsilyl)ethoxy]methyl}-2,3,4,7-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-
d]pyrimidin-1-yl)cyclohexyl]methyl}amino)-4,4,4-trifluorobutanenitrile obtained in
Reference Synthetic Example 9, and that (R)-4,4,4-trifluoro-3-[({trans-4-[7-
30 (hydroxymethyl)-4-oxo-4,7-dihydro-1H-pyrrolo[2,3-h][1,6]naphthyridin-1-
yl]cyclohexyl}methyl)amino]butanenitrile (LC/MS: measurement condition 4, retention
time = 1.76 min, LC/MS(ESI+) m/z; 448 [M+H]+) was obtained as an intermediate, and
38
the reaction mixture was extracted by adding a solvent mixture of chloroform /
isopropanol (= 1/1 (v/v)) and water. The organic layer was washed with saturated
aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under
reduced pressure. The residue was purified by silica gel column chromatography
(chloroform/methanol = 1/0 1/1 (v/v), followed by HiFlash (registered trademar5 k)
column amino type manufactured by Yamazen Corporation:ethyl acetate/methanol = 1/0
10/1 (v/v)) to give the title compound as a white solid (634 mg, yield 82%).
SYNTHETIC EXAMPLE 4
1-{trans-4-[(4-Methyl-1H-pyrazol-1-yl)methyl]cyclohexyl}-1H-pyrrolo[2,3-
10 h][1,6]naphthyridin-4(7H)-one
The reactions in Synthetic Example 1 were carried out in substantially the same
manners except that 1-{trans-4-[(4-methyl-1H-pyrazol-1-yl)methyl]cyclohexyl}-7-{[2-
(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one (1.33 g, 2.70
mmol) obtained in Reference Synthetic Example 24 was used instead of (R)-3-({[trans-
15 4-(2,4-dioxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-2,3,4,7-tetrahydro-1Hpyrrolo[
3’,2’:5,6]pyrido[4,3-d]pyrimidin-1-yl)cyclohexyl]methyl}amino)-4,4,4-
trifluorobutanenitrile obtained in Reference Synthetic Example 9, and that 7-
(hydroxymethyl)-1-{trans-4-[(4-methyl-1H-pyrazol-1-yl)methyl]cyclohexyl}-1Hpyrrolo[
2,3-h][1,6]naphthyridin-4(7H)-one (LC/MS: measurement condition 2, retention
20 time = 1.64 min, LC/MS(ESI+) m/z; 392 [M+H]+) was obtained as an intermediate.
Then, the reaction mixture was extracted by adding ethyl acetate and water, and the
organic layer was washed with saturated aqueous sodium chloride, dried over
anhydrous sodium sulfate and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (HiFlash (registered trademark) column
25 amino type manufactured by Yamazen Corporation: ethyl acetate) twice. The resulting
solid was washed with ethyl acetate to give the title compound as a white solid (521 mg,
yield 53%).
SYNTHETIC EXAMPLE 5
1-{trans-4-[(2,2,2-Trifluoroethoxy)methyl]cyclohexyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-
30 4(7H)-one
The reactions in Synthetic Example 1 were carried out in substantially the same
manners except that the mixture (9.2 mg) containing 1-{trans-4-[(2,2,2-
39
trifluoroethoxy)methyl]cyclohexyl}-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-
h][1,6]naphthyridin-4(7H)-one (138 mg, 0.271 mmol) obtained in Reference Synthetic
Example 25 was used instead of (R)-3-({[trans-4-(2,4-dioxo-7-{[2-
(trimethylsilyl)ethoxy]methyl}-2,3,4,7-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-
d]pyrimidin-1-yl)cyclohexyl]methyl}amino)-4,4,4-trifluorobutanenitrile obtained i5 n
Reference Synthetic Example 9, and that 7-(hydroxymethyl)-1-{trans-4-[(2,2,2-
trifluoroethoxy)methyl]cyclohexyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one (LC/MS:
measurement condition 2, retention time = 1.95 min, LC/MS(ESI+) m/z; 410 [M+H]+) was
obtained as an intermediate. Then, the reaction mixture was concentrated under
10 reduced pressure, and the residue was purified by silica gel thin layer chromatography
(ethyl acetate/hexane = 5/1 (v/v)) to give the title compound as a white solid (3.8 mg,
yield 21% (two steps)).
SYNTHETIC EXAMPLE 6
1-{trans-4-[(3,3,3-Trifluoropropoxy)methyl]cyclohexyl}-1H-pyrrolo[2,3-
15 h][1,6]naphthyridin-4(7H)-one
The reactions in Synthetic Example 1 were carried out in substantially the same
manners except that 1-{trans-4-[(3,3,3-trifluoropropoxy)methyl]cyclohexyl}-7-{[2-
(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one (1.47 g, 2.80
mmol) obtained in Reference Synthetic Example 26 was used instead of (R)-3-({[trans-
20 4-(2,4-dioxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-2,3,4,7-tetrahydro-1Hpyrrolo[
3’,2’:5,6]pyrido[4,3-d]pyrimidin-1-yl)cyclohexyl]methyl}amino)-4,4,4-
trifluorobutanenitrile obtained in Reference Synthetic Example 9, and that 7-
(hydroxymethyl)-1-{trans-4-[(3,3,3-trifluoropropoxy)methyl]cyclohexyl}-1H-pyrrolo[2,3-
h][1,6]naphthyridin-4(7H)-one (LC/MS: measurement condition 2, retention time = 1.94
25 min, LC/MS(ESI+) m/z; 424 [M+H]+) was obtained as an intermediate. Then, the
reaction mixture was extracted by adding chloroform and water, and the organic layer
was washed with saturated aqueous sodium chloride, dried over anhydrous sodium
sulfate and concentrated under reduced pressure. The residue was purified by silica
gel column chromatography (ethyl acetate/methanol = 1/0 95/5 (v/v), followed by
30 chloroform/methanol = 95/5 20/80 (v/v)) to give the title compound as a white solid
(1.09 g, yield 98%).
SYNTHETIC EXAMPLE 7
40
(R)-4,4,4-Trifluoro-3-{[trans-4-(4-oxo-4,7-dihydro-1H-pyrrolo[2,3-h][1,6]naphthyridin-1-
yl)cyclohexyl]methoxy}butanenitrile
4,4,4-Trifluoro-3-{[trans-4-(4-oxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydro-
1H-pyrrolo[2,3-h][1,6]naphthyridin-1-yl)cyclohexyl]methoxy}butanenitrile (1.29 g, 2.35
mmol) obtained in Reference Synthetic Example 27 was purified by preparative hig5 h
performance liquid chromatography (CHIRALPAK (registered trademark) IB 5 m
20×250 mm: hexane/ethanol = 80/20 50/50 (v/v): flow rate 12 mL/min), and the
fraction containing a single optically active isomer eluted at a retention time of 27.49
minutes was concentrated to give (R)-4,4,4-trifluoro-3-{[trans-4-(4-oxo-7-{[2-
10 (trimethylsilyl)ethoxy]methyl}-4,7-dihydro-1H-pyrrolo[2,3-h][1,6]naphthyridin-1-
yl)cyclohexyl]methoxy}butanenitrile (490 mg). Then, the reactions in Synthetic
Example 1 were carried out in substantially the same manners except that (R)-4,4,4-
trifluoro-3-{[trans-4-(4-oxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydro-1Hpyrrolo[
2,3-h][1,6]naphthyridin-1-yl)cyclohexyl]methoxy}butanenitrile (490 mg, 0.893
15 mmol) obtained above was used instead of (R)-3-({[trans-4-(2,4-dioxo-7-{[2-
(trimethylsilyl)ethoxy]methyl}-2,3,4,7-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-
d]pyrimidin-1-yl)cyclohexyl]methyl}amino)-4,4,4-trifluorobutanenitrile obtained in
Reference Synthetic Example 9, and that (R)-4,4,4-trifluoro-3-({trans-4-[7-
(hydroxymethyl)-4-oxo-4,7-dihydro-1H-pyrrolo[2,3-h][1,6]naphthyridin-1-
20 yl]cyclohexyl}methoxy)butanenitrile (LC/MS: measurement condition 4, retention time =
1.92 min, LC/MS(ESI+) m/z; 449 [M+H]+) was obtained as an intermediate. Then, the
reaction mixture was extracted by adding ethyl acetate and water, and the organic layer
was washed with saturated aqueous sodium chloride and concentrated under reduced
pressure. The residue was purified by silica gel column chromatography (HiFlash
25 (registered trademark) column amino type manufactured by Yamazen Corporation: ethyl
acetate/methanol = 1/0 92/8 (v/v)) to give the title compound as a white solid (299
mg, yield 30% (two steps)).
The structures of the respective compounds obtained in Reference Synthetic
Example are shown below.
41
The structures of the respective compounds obtained in Synthetic Example are
shown below.
42
The physical property data on the compounds obtained the Reference Synthetic
Examples and Synthetic Examples are shown below.
Rf5 1
LC/MS: measurement condition 2, retention time = 2.25 min
LC/MS(ESI+) m/z; 292 [M+H]+
Rf2
LC/MS: measurement condition 2, retention time = 1.92 min
10 LC/MS(ESI+) m/z; 278 [M+H]+
Rf3
LC/MS: measurement condition 2, retention time = 1.93 min
LC/MS(ESI+) m/z; 264 [M+H]+
Rf4
15 LC/MS: measurement condition 2, retention time = 2.66 min
LC/MS(ESI+) m/z; 360 [M+H]+
Rf5
LC/MS: measurement condition 2, retention time = 1.29 min
LC/MS(ESI+) m/z; 226 [M+H]+
20 Rf6
1H-NMR (CDCl3) : 0.00 (s, 9H), 0.98 (t, J = 8.2 Hz, 2H), 1.09-1.29 (m, 2H), 1.36-1.87
(m, 2H), 1.94-2.19 (m, 4H), 2.61 (d, J = 6.5 Hz, 2H), 2.68-2.88 (m, 2H), 3.60 (t, J = 8.4
Hz, 2H), 3.86 (s, 2H), 4.66-4.81 (m, 1H),5.78 (s, 2H), 6.73 (d, J = 3.7 Hz, 1H), 7.36-7.41
(m, 5H), 7.46 (d, J = 3.7 Hz, 1H), 9.09 (s, 1H).
25 Rf7
43
1H-NMR (DMSO-d6) : -0.07 (s, 9H), 0.84 (t, J = 8.0 Hz, 2H), 1.05-1.21 (m, 2H), 1.27-
1.45 (m, 1H), 1.88-1.97 (m, 4H), 2.35-2.69 (m, 4H), 3.54 (t, J = 8.2 Hz, 2H), 4.51-4.68
(m, 1H), 5.69 (s, 2H), 6.69 (d, J = 3.7 Hz, 1H), 7.79 (d, J = 3.7 Hz, 1H), 8.79 (s, 1H).
Rf8
1H-NMR (DMSO-d6) : -0.07 (s, 9H), 0.84 (t, J = 8.0 Hz, 2H), 1.05-1.21 (m, 2H), 1.375 -
1.52 (m, 1H), 1.86-2.03 (m, 4H), 2.51-2.65 (m, 2H), 2.82 (dd, J = 16.8, 8.2 Hz, 2H), 2.92
(dd, J = 16.8, 5.3 Hz, 2H), 3.54 (t, J = 8.2 Hz, 2H), 3.67-3.80 (m, 1H), 4.54-4.67 (m, 1H),
5.69 (s, 2H), 6.69 (d, J = 4.1 Hz, 1H), 7.79 (d, J = 4.1 Hz, 1H), 8.79 (s, 1H), 11.53 (br s,
1H).
10 LC/MS: measurement condition 1, retention time = 4.59 min
LC/MS(ESI+) m/z; 565 [M+H]+
LC/MS(ESI-) m/z; 563 [M-H]-
Rf9
1H-NMR (CDCl3) : -0.05 (s, 9H), 0.87-0.98 (m, 2H), 1.10-1.28 (m, 3H), 1.96-2.06 (m,
15 2H), 2.07-2.20 (m, 2H), 2.56-2.89 (m, 6H), 3.39-3.48 (m, 1H), 3.52-3.59 (m, 2H), 4.64-
4.76 (m, 1H), 5.73 (s, 2H), 6.69 (d, J = 3.7 Hz, 1H), 7.43 (d, J = 4.1 Hz, 1H), 8.06 (br s,
1H), 9.04 (s, 1H).
Rf10
1H-NMR (CDCl3) : -0.04 (s, 9H), 0.94 (t, J = 8.3 Hz, 2H), 1.20-1.41 (m, 2H) , 1.60-1.72
20 (m, 1H), 1.98-2.19 (m, 4H), 2.81 (q, J = 11.9 Hz, 2H), 3.56 (t, J = 8.3 Hz, 2H), 4.34 (d, J
= 6.3 Hz, 2H), 4.67-4.82 (m, 1H), 5.74 (s, 2H), 6.66 (d, J = 4.2 Hz, 1H), 7.09-7.10 (m,
1H), 7.44-7.45 (m, 2H), 8.13 (br s, 1H), 8.16 (s, 1H), 9.05 (s, 1H).
LC/MS: measurement condition 2, retention time = 2.47 min
LC/MS(ESI+) m/z; 539 [M+H]+
25 Rf11
1H-NMR (CDCl3) : -0.05 (s, 9H), 0.00 (s, 9H), 0.88-1.07 (m, 4H), 1.14-1.40 (m, 2H),
1.64-1.79 (br m, 1H), 1.94-2.15 (m, 4H), 2.70-2.89 (m, 2H), 3.51-3.65 (m, 4H), 3.73 (t, J
= 8.3 Hz, 2H), 4.62-4.77 (br m, 1H), 5.52 (s, 2H), 5.73 (s, 2H), 6.68 (d, J = 3.6 Hz, 1H),
7.41 (d, J = 3.6 Hz, 1H), 9.08 (s, 1H).
30 LC/MS: measurement condition 3, retention time = 2.41 min
LC/MS(ESI+) m/z; 575 [M+H]+
Rf12
44
1H-NMR (CDCl3) : -0.05 (s, 9H), -0.01 (s, 9H), 0.87-1.03 (m, 2H), 1.16-1.30 (m, 4H),
1.71-1.84 (br m, 1H), 1.93-2.06 (m, 4H), 2.33-2.50 (m, 2H), 2.68-2.84 (m, 2H), 3.34 (d, J
= 6.0 Hz, 2H), 3.51-3.60 (m, 2H), 3.62-3.76 (m, 4H), 4.60-4.74 (br m, 1H), 5.51 (s, 2H),
5.72 (s, 2H), 6.67 (d, J = 3.9 Hz, 1H), 7.40 (d, J = 3.9 Hz, 1H), 9.07 (s, 1H).
LC/MS: measurement condition 3, retention time = 2.85 mi5 n
LC/MS(ESI+) m/z; 671 [M+H]+
Rf13
1H-NMR (CDCl3) : -0.06 (s, 9H), 0.89-0.94 (m, 2H), 3.40-3.56 (m, 8H), 5.68 (s, 2H),
6.68 (d, J = 3.6 Hz, 1H), 7.44 (d, J = 3.6 Hz, 1H), 8.29 (s, 1H).
10 LC/MS: measurement condition 2, retention time = 2.62 min
LC/MS(ESI+) m/z; 370 [M+H]+
Rf14
1H-NMR (CD3OD) : -0.05 (s, 9H), 0.91 (t, J = 8.5 Hz, 2H), 3.51 (s, 1H), 3.54 (t, J = 8.5
Hz, 2H), 5.69 (s, 2H), 6.78 (d, J = 3.8 Hz, 1H), 7.44 (d, J = 3.8 Hz, 1H), 9.14 (s, 1H).
15 LC/MS: measurement condition 2, retention time = 2.93 min
LC/MS(ESI+) m/z; 335 [M+H]+
Rf15
LC/MS: measurement condition 2, retention time = 2.14 min
LC/MS(ESI+) m/z; 428 [M+H]+
20 Rf16
Rf16-1
LC/MS: measurement condition 4, retention time = 2.75 min
LC/MS(ESI+) m/z; 335 [M+H]+
Rf16-2
25 LC/MS: measurement condition 4, retention time = 3.12 min
LC/MS(ESI+) m/z; 396 [M+H]+
Rf17
1H-NMR (CDCl3) : -0.06 (s, 9H), 0.90-0.96 (m, 2H), 1.41 (qd, J = 12.3, 3.3 Hz, 2H),
1.66-1.71 (m,1H), 1.86 (qd, J = 12.3, 3.3 Hz, 2H), 2.12-2.17 (m, 2H), 2.30-2.33 (m, 2H),
30 3.53-3.59 (m, 2H), 3.63 (d, J = 6.0 Hz, 2H), 4.93 (tt, J = 12.3, 3.3 Hz, 1H), 5.80 (s, 2H),
6.43 (d, J = 8.1 Hz, 1H), 6.78 (d, J = 3.9 Hz, 1H), 7.43 (d, J = 3.3 Hz, 1H), 7.76 (d, J =
8.1 Hz, 1H), 9.40 (s, 1H).
45
LC/MS: measurement condition 2, retention time = 2.16 min
LC/MS(ESI+) m/z; 428 [M+H]+
Rf18
1H-NMR (CDCl3) : -0.06 (s, 9H), 0.90-0.96 (m, 2H), 1.67 (qd, J = 12.9, 3.3 Hz, 2H),
1.91 (qd, J = 12.9, 3.3 Hz, 2H), 2.34-2.52 (m, 5H), 3.53-3.60 (m, 2H), 4.94 (tt, J = 11.85 ,
2.9 Hz, 1H), 5.80 (s, 2H), 6.44 (d, J = 8.1 Hz, 1H), 6.74 (d, J = 3.7 Hz, 1H), 7.44 (d, J =
3.7 Hz, 1H), 7.73 (d, J = 8.1 Hz, 1H), 9.40 (s, 1H), 9.78 (s, 1H).
LC/MS: measurement condition 2, retention time = 2.30 min
LC/MS(ESI+) m/z; 426 [M+H]+
10 Rf19
1H-NMR (CDCl3) : -0.06 (s, 9H), 0.88-0.96 (m, 2H), 1.33 (qd, J = 12.6, 3.3 Hz, 2H),
1.57-1.71 (m, 1H), 1.84 (qd, J = 12.6, 3.3 Hz, 2H), 2.11-2.21 (m, 2H), 2.23-2.33 (m, 2H),
2.62 (d, J = 6.6 Hz, 2H), 3.52-3.59 (m, 2H), 3.83 (s, 2H), 4.91 (tt, J = 11.9, 3.3 Hz, 1H),
5.80 (s, 2H), 6.43 (d, J = 7.9 Hz, 1H), 6.77 (d, J = 3.6 Hz, 1H), 7.32-7.37 (m, 5H), 7.42
15 (d, J = 3.6 Hz, 1H), 7.76 (d, J = 7.9 Hz, 1H), 9.40 (s, 1H).
LC/MS: measurement condition 1, retention time = 3.19 min
LC/MS(ESI+) m/z; 517 [M+H]+
Rf20
1H-NMR (CDCl3) : -0.06 (s, 9H), 0.89-0.96 (m, 2H), 1.29-1.56 (m, 3H), 1.85 (qd, J =
20 12.3, 2.9 Hz, 2H), 2.10-2.19 (m, 2H), 2.26-2.35 (m, 2H), 2.71 (d, J = 6.1 Hz, 2H), 3.53-
3.59 (m, 2H), 4.92 (tt, J = 11.9, 3.3 Hz, 1H), 5.79 (s, 2H), 6.42 (d, J = 8.2 Hz, 1H), 6.77
(d, J = 3.7 Hz, 1H), 7.42 (d, J = 3.7 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H), 9.40 (s, 1H).
LC/MS: measurement condition 1, retention time = 2.89 min
LC/MS(ESI+) m/z; 427 [M+H]+
25 Rf21
1H-NMR (CDCl3) : -0.06 (s, 9H), 0.90-0.96 (m, 2H), 1.33-1.46 (m, 3H), 1.53-1.63 (m,
1H), 1.78-1.93 (m, 2H), 2.14-2.23 (m, 2H), 2.27-2.36 (m, 2H), 2.58-2.96 (m, 4H), 3.40-
3.51 (m, 1H), 3.53-3.60 (m, 2H), 4.88-4.99 (m, 1H), 5.80 (s, 2H), 6.44 (d, J = 8.3 Hz,
1H), 6.77 (d, J = 4.0 Hz, 1H), 7.43 (d, J = 4.0 Hz, 1H), 7.75 (d, J = 8.3 Hz, 1H), 9.41 (s,
30 1H).
LC/MS: measurement condition 1, retention time = 4.40 min
LC/MS(ESI+) m/z; 548 [M+H]+
46
Rf22
1H-NMR (CDCl3) : -0.06 (s, 9H), 0.89-0.97 (m, 2H), 1.30-1.48 (m, 3H), 1.54-1.67 (m,
1H), 1.77-1.94 (m, 2H), 2.14-2.23 (m, 2H), 2.26-2.36 (m, 2H), 2.58-2.96 (m, 4H), 3.40-
3.51 (m, 1H), 3.52-3.61 (m, 2H), 4.93 (tt, J = 11.8, 2.9 Hz, 1H), 5.80 (s, 2H), 6.43 (d, J =
8.1 Hz, 1H), 6.77 (d, J = 3.7 Hz, 1H), 7.43 (d, J = 3.7 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H)5 ,
9.40 (s, 1H).
LC/MS: measurement condition 2, retention time = 2.68 min
LC/MS(ESI+) m/z; 548 [M+H]+
Rf23
10 1H-NMR (CDCl3) : -0.06 (s, 9H), 0.93 (t, J = 8.4 Hz, 2H), 1.41-1.56 (m, 2H), 1.82-1.97
(m, 3H), 2.15-2.20 (m, 2H), 2.32-2.36 (m, 2H), 3.07 (s, 3H), 3.56 (t, J = 8.4 Hz, 2H),
4.18 (d, J = 6.0 Hz, 2H), 4.94 (tt, J = 12.0, 3.3 Hz 1H), 5.80 (s, 2H), 6.43 (d, J = 7.8 Hz,
1H), 6.73 (d, J = 3.9 Hz, 1H), 7.43 (d, J = 3.9 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H), 9.39 (s,
1H).
15 LC/MS: measurement condition 4, retention time = 2.42 min
LC/MS(ESI+) m/z; 506 [M+H]+
Rf24
1H-NMR (CDCl3) : -0.06 (s, 9H), 0.90-0.95 (m, 2H), 1.39 (qd, J = 12.3, 2.4 Hz, 2H),
1.83 (qd, J = 12.3, 3.0 Hz, 2H), 1.95-2.07 (m, 3H), 2.09 (s, 3H), 2.26-2.30 (m, 2H), 3.53-
20 3.59 (m, 2H), 4.02 (d, J = 6.9 Hz, 2H), 4.91 (tt, J = 12.0, 3.0 Hz, 1H), 5.80 (s, 2H), 6.42
(d, J = 8.1 Hz, 1H), 6.74 (d, J = 3.9 Hz, 1H), 7.17 (s, 1H), 7.34 (s, 1H), 7.43 (d, J = 3.9
Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 9.39 (s, 1H).
LC/MS: measurement condition 4, retention time = 2.62 min
LC/MS(ESI+) m/z; 492 [M+H]+
25 Rf25
LC/MS: measurement condition 2, retention time = 2.80 min
LC/MS(ESI+) m/z; 510 [M+H]+
Rf26
1H-NMR (CDCl3) : -0.05 (s, 9H), 0.93 (t, J = 8.5 Hz, 2H), 1.33-1.45 (m, 2H), 1.76-1.91
30 (m, 3H), 2.11-2.15 (m, 2H), 2.27-2.31 (m, 2H), 2.43 (qt, J = 10.5, 6.0 Hz, 2H), 3.39 (d, J
= 6.0 Hz, 2H), 3.56 (t, J = 8.5 Hz, 2H), 3.68 (t, J = 6.6 Hz, 2H), 4.88-4.96 (m, 1H), 5.81
(s, 2H), 6.43 (d, J = 8.1 Hz, 1H), 6.78 (d, J = 3.6 Hz, 1H), 7.44 (d, J = 3.6 Hz, 1H), 7.76
47
(d, J = 8.1 Hz, 1H), 9.41 (s, 1H).
Rf27
1H-NMR (CDCl3) : -0.06 (s, 9H), 0.93 (t, J = 8.2 Hz, 2H), 1.37-1.57 (m, 2H), 1.78-1.95
(m, 3H), 2.12-2.23 (m, 2H), 2.26-2.37 (m, 2H), 2.77 (d, J = 6.6 Hz, 2H), 3.56 (t, J = 8.3
Hz, 2H), 3.65-3.76 (m, 1H), 3.77-3.87 (m, 1H), 4.01 (dt, J = 6.0, 12.1 Hz, 1H), 4.85-4.95 9
(m, 1H), 5.80 (s, 2H), 6.43 (d, J = 8.1 Hz, 1H), 6.77 (d, J = 3.7 Hz, 1H), 7.43 (d, J = 3.7
Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 9.40 (s, 1H).
Rf28
Rf28-1
10 LC/MS: measurement condition 2, retention time = 2.93 min
LC/MS(ESI+) m/z; 335 [M+H]+
Rf28-2
LC/MS: measurement condition 2, retention time = 3.45 min
LC/MS(ESI+) m/z; 406 [M+H]+
15 Rf29
1H-NMR (CDCl3) : -0.06 (s, 9H), 0.90-0.96 (m, 2H), 1.41 (qd, J = 12.6, 3.3 Hz, 2H),
1.66-1.71 (m,1H), 1.86 (qd, J = 12.3, 3.3 Hz, 2H), 2.12-2.17 (m, 2H), 2.30-2.33 (m, 2H),
3.53-3.59 (m, 2H), 3.64 (d, J = 6.0 Hz, 2H), 4.93 (tt, J = 12.3, 3.3 Hz, 1H), 5.80 (s, 2H),
6.44 (d, J = 8.1 Hz, 1H), 6.79 (d, J = 3.6 Hz, 1H), 7.43 (d, J = 3.6 Hz, 1H), 7.77 (d, J =
20 8.1 Hz, 1H), 9.40 (s, 1H).
LC/MS: measurement condition 2, retention time = 2.15 min
LC/MS(ESI+) m/z; 428 [M+H]+
Ex1
1H-NMR (DMSO-d6) : 1.00-1.21 (m, 2H), 1.34-1.52 (m, 1H), 1.80-2.07 (m, 4H), 2.48-
25 2.69 (m, 4H), 2.72-2.98 (m, 2H), 3.63-3.81 (m, 1H), 4.55-4.72 (m, 1H), 6.62 (d, J = 3.6
Hz, 1H), 7.59 (d, J = 3.6 Hz, 1H), 8.73 (s, 1H), 10.80 (br s, 1H).
LC/MS: measurement condition 2, retention time = 1.91 min
LC/MS(ESI+) m/z; 435 [M+H]+
LC/MS(ESI-) m/z; 433 [M-H]-
30 Ex2
1H-NMR (DMSO-d6) : 1.16 (q, J = 11.8 Hz, 2H), 1.52-1.68 (br m, 1H), 1.89 (d, J = 10.2
Hz, 4H), 2.49-2.63 (m, 4H), 3.22-3.43 (m, 2H), 3.60 (t, J = 6.0 Hz, 2H), 4.55-4.69 (t, J =
48
12.0 Hz, 1H), 6.59 (d, J = 3.6 Hz, 1H), 7.59 (d, J = 3.6 Hz, 1H), 8.72 (s, 1H), 12.35 (br s,
1H).
LC/MS: measurement condition 3, retention time = 1.30 min
LC/MS(ESI+) m/z; 411 [M+H]+
LC/MS(ESI-) m/z; 409 [M-5 H]-
Ex3
1H-NMR (DMSO-d6) : 1.23-1.39 (m, 2H), 1.45-1.59 (m, 1H), 1.84-1.99 (m, 2H), 2.00-
2.14 (m, 4H), 2.56-2.69 (m, 2H), 2.79-2.98 (m, 2H), 3.66-3.79 (m, 1H), 4.83-4.95 (m,
1H), 6.20 (d, J = 8.1 Hz, 1H), 6.80 (dd, J = 3.3, 1.8 Hz, 1H), 7.58 (t, J = 3.3 Hz, 1H),
10 8.17 (d, J = 8.1 Hz, 1H), 9.02 (s, 1H), 12.32 (s, 1H).
LC/MS: measurement condition 2, retention time = 1.83 min
LC/MS(ESI+) m/z; 418 [M+H]+
LC/MS(ESI-) m/z; 416 [M-H]-
Ex4
15 1H-NMR (CD3OD) : 1.41-1.55 (m, 2H), 1.86-2.05 (m, 5H), 2.10 (s, 3H), 2.23-2.28 (m,
2H), 4.06 (d, J = 7.2 Hz, 2H), 5.05-5.15 (m, 1H), 6.45 (d, J = 7.8 Hz, 1H), 6.94 (d, J =
3.6 Hz, 1H), 7.32 (s, 1H), 7.44(s, 1H), 7.56 (d, J = 3.6 Hz, 1H), 8.27 (d, J = 8.1 Hz, 1H)
9.20 (s, 1H).
LC/MS: measurement condition 2, retention time = 1.72 min
20 LC/MS(ESI+) m/z; 362 [M+H]+
Ex5
1H-NMR (CDCl3) : 1.35-1.47 (m, 2H), 1.75-1.91 (m, 3H), 2.10-2.22 (m, 2H), 2.30-2.40
(m, 2H), 3.58 (d, J = 5.9 Hz, 2H), 3.87 (q, J = 8.6 Hz, 2H) 4.92-5.06 (m, 1H), 6.47 (d, J =
7.9 Hz, 1H), 6.77-6.82 (m, 1H), 7.47-7.50 (m, 1H), 7.79 (d, J = 8.3 Hz, 1H), 9.44 (s, 1H),
25 11.90 (bs, 1H).
LC/MS: measurement condition 2, retention time = 1.97 min
LC/MS(ESI+) m/z; 380 [M+H]+
Ex6
LC/MS: measurement condition 2, retention time = 1.99 min
30 LC/MS(ESI+) m/z; 394 [M+H]+
Ex7
1H-NMR (DMSO-d6) : 1.29-1.49 (m, 2H), 1.67-2.16 (m, 7H), 2.95-3.24 (m, 2H), 3.64
49
(dd, J = 6.5, 2.3 Hz, 2H), 4.47-4.61 (m, 1H), 4.82-4.97 (m, 1H), 6.21 (d, J = 7.8 Hz, 1H),
6.80 (d, J = 3.3 Hz, 1H), 7.58 (d, J = 2.7 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 9.01 (s, 1H),
12.31 (br s, 1H).
LC/MS: measurement condition 2, retention time = 1.88 min
LC/MS(ESI+) m/z; 419 [M+5 H]+
LC/MS(ESI-) m/z; 417 [M-H]-
Pharmacological assay
Now, a pharmacological assay of the tricyclic pyrimidine compounds of the
10 present invention will be described.
1. Enzyme Assay
The JAK inhibitory activities of compounds of the present invention were
measured.
The enzymes (JAK1, JAK2, JAK3 and Tyk2) were purchased from Carna
15 Biosciences, Inc.
As the substrate for the enzymes (hereinafter referred to as the substrate),
LANCE Ultra ULight-JAK-1 (Tyr1023) Peptide (manufactured by PerkinElmer Co., Ltd.)
was used.
As the antibody for detecting phosphorylation of the substrate, LANCE Ultra
20 Europium-anti-phospho tyrosine antibody (PT66) (manufactured by PerkinElmer Co.,
Ltd.) was used.
The other reagents are purchased from the following suppliers.
Adenosine triphosphate (ATP): Sigma-Aldrich
4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES): DOJINDO
25 LABORATORIES
Glycol ether diamine tetraacetic acid (EGTA): DOJINDO LABORATORIES
Magnesium chloride (MgCl2): Wako Pure Chemical Industries, Ltd.
Dithiothreitol (DTT): Wako Pure Chemical Industries, Ltd.
Tween 20: Sigma-Aldrich
30 Ethylenediaminetetraacetic acid (EDTA): DOJINDO LABORATORIES
The compounds of the present invention, the enzymes (JAK1, JAK2, JAK3 and
Tyk2), the substrate and ATP were used for the assays after diluted with the assay
50
buffer.
The composition of the assay buffer is given below.
HEPES (pH7.5): 50 mM
EGTA: 1 mM
MgCl2: 10 m5 M
DTT: 2 mM
Tween 20: 0.01% (wt/wt)
Dilutions were made at such concentrations and dispensed on a well plate, which
will be described later, in such volumes that the following final concentrations would be
10 achieved on the well plate.
Each compound was used at six consecutive concentrations among the 11
concentrations of 1 M , 0.3 M , 0.1 M , 0.03 M , 0.01 M , 0.003 M , 0.001 M ,
0.0003 M , 0.0001 M , 0.00003 M and 0.00001 M.
The enzyme concentrations and the ATP concentrations in the respective enzyme
15 (JAK1, JAK2, JAK3 and Tyk2) assays were as follows.
JAK1 enzyme assay; the enzyme concentration was 0.5 µg/mL, and the ATP
concentration was 70 µM.
JAK2 enzyme assay; the enzyme concentration was 0.013 µg/mL, and the ATP
concentration was 10 µM.
20 JAK3 enzyme assay; the enzyme concentration was 0.020 µg/mL, and the ATP
concentration was 3 µM.
Tyk2 enzyme assay; the enzyme concentration was 0.25 µg/mL and the ATP
concentration was 20 µM.
The concentration of the substrate for the enzymes was 25 nM.
25 The concentration of EDTA was 15 mM.
The concentration of PT66 was 2 nM.
Dilute solutions of compounds and enzymes were dispensed into wells of a 384-
well black plate (manufactured by Greiner bio-one) and preincubated at room
temperature for 5 minutes.
30 Then, a dilute solution of the substrate and then a dilute solution of ATP were
added, and the plate was incubated at room temperature for 30 minutes.
Then, a dilute solution of EDTA and then a dilute solution of PT66 were added,
51
and the plate was incubated at room temperature for 1 hour.
The fluorescences were measured with ARVO-HTS, and from the plot of logarithm
of a compound concentration and inhibitory activity, the IC50 value was calculated.
The results of JAK1, JAK2, JAK3 and Tyk2 enzyme assays of the compounds of
Synthetic Examples 1 to 7 are shown in Table 15 .
As shown below in Table 1, the compounds of the present invention have
favorable inhibitory activity against JAKs.
[TABLE 1]
10
2. Signal assay in rat whole blood
The inhibitory activities of the compounds of the present invention obtained in
Synthetic Examples 1 and 2 against cytokine signaling via JAK were measured by STAT
phosphorylation assay using rat whole blood.
15 Female Lewis rats were purchased from CHARLES RIVER LABORATORIES
JAPAN, INC.
Rat IL-6 was purchased from PeproTech.
FITC (fluorescein isothiocyanate)-labeled anti-CD3 antibody (FITC-CD3) was
purchased from eBioscience.
20 BD Phosflow Lyse/Fix Buffer, BD Phosflow Perm Buffer III, BD Pharmingen Stain
Buffer and BD Phosflow STAT-1 (pY701) PE (R-Phycoerythrin) fluorescently labeled
antibody (hereinafter referred to as BD Phosflow STAT-1) were purchased from BD
(Becton, Dickinson and Company).
Dilutions were made at such concentrations and dispensed into tubes, which will
25 be described later, in such volumes that the following final concentrations would be
achieved in the tubes.
52
Each compound was used at three consecutive concentrations of 1 M, 0.1 M
and 0.01 M, or 10 M, 1 M and 0.1 M.
The concentration of rat IL-6 was 100 ng/mL.
The concentration of FITC-CD3 was 1 µg/mL.
Blood was collected from the inferior vena cava of a female Lewis rat. The bloo5 d
and a compound were put into each Costar assay block tube and incubated at 37 C for
15 minutes, then incubated with FITC-CD3 at 37 C for 15 minutes, incubated with rat IL-
6 at 37 C for 15 minutes and incubated with 10 times as much of BD Phosflow Lyse/Fix
Buffer as the blood at 37 C for 12 minutes. Centrifugal separation was carried out at
10 5,884 m/s2 for 6 minutes with a centrifugal separator to precipitate the cells, and the
supernatants were removed.
The cell pellets were washed with 1 mL of phosphate buffered saline (PBS), then
incubated with 0.6 mL of BD Phosflow Perm Buffer III on ice for 30 minutes and
centrifuged at 5,884 m/s2 for 6 minutes by means of a centrifugal separator to
15 precipitate the cells, and the supernatants were removed.
The cell pellets were washed with 0.3 mL of BD Pharmingen Stain Buffer and
incubated with 0.1 mL of BD Pharmingen Stain Buffer and 10 L of BD Phosflow STAT-
1 at room temperature for 30 minutes. After addition of 0.1 mL of BD Pharmingen
Stain Buffer, the cells were centrifuged at 5,884 m/s2 for 6 minutes by means of a
20 centrifugal separator to precipitate the cells, and the supernatants were removed.
The cell pellets were washed with 0.3 mL of BD Pharmingen Stain Buffer, and
0.12 mL of BD Pharmingen Stain Buffer was added. The cytokine signaling inhibition
was measured with FACS CantoII (manufactured by BD) by detecting FITC-labeled
CD3 positive T cells and detecting the amount of phosphated STAT-1 protein in the cells
25 as the PE fluorescence. From the plot of the logarithm of a compound concentration
and inhibitory activity, the IC50 value was calculated. The results of rat whole blood
signal assays of the compounds of Synthetic Examples 1 and 2 are shown in Table 2.
53
[TABLE 2]
Excellent inhibitory activity in the rat whole blood signal assay is favorable for high
effectiveness against diseases against which inhibition of JAK is effective, especially
rheumatoid arthriti5 s.
The compounds of the present invention showed excellent inhibitory activities
against JAK signaling by cytokine stimulation in rat whole blood by means of the JAK
inhibitory activity.
Further, the results of the rat whole blood signal assay of compound A (Exampleb
10 102), Compound B (Exampleb 116), Compound C (Exampleb 122) and Compound D
(Exampleb 127) disclosed in WO2013/024895 are shown in Table 3.
[TABLE 3]
15 3. Signal assay in human whole blood
The inhibitory activities of the compounds of the present invention obtained in
Synthetic Examples 3 to 7 against cytokine signaling via JAK were measured by STAT
phosphorylation assay using human whole blood.
Human whole blood was collected from healthy humans.
20 Human IL-6 was purchased from R&D systems.
FITC (fluorescein isothiocyanate)-labeled anti-human CD3 antibody (FITC-hCD3)
was purchased from BD (Becton, Dickinson and Company).
54
BD Phosflow Lyse/Fix Buffer, BD Phosflow Perm Buffer III, BD Pharmingen Stain
Buffer and BD Phosflow STAT-1(pY701) PE (R-Phycoerythrin) fluorescently labeled
antibody (hereinafter referred to as BD Phosflow STAT-1) were purchased from BD
(Becton, Dickinson and Company).
Dilutions were made at such concentrations and dispensed into tubes, which wil5 l
be described later, in such volumes that the following final concentrations would be
achieved in the tubes.
Each compound was used at six concentrations of 3 M, 1.5 M, 0.75 M, 0.38
M, 0.19 M and 0.093 M, at six concentrations of 2 M, 1 M, 0.5 M, 0.25 M, 0.13
10 M and 0.063 M, or at six concentrations of 10 M, 5 M, 2.5 M, 1.25 M, 0.63 M
and 0.31 M.
The concentration of human IL-6 was 100 ng/mL.
Human blood and a compound were put into each Costar assay block tube and
incubated at 37°C for 30 minutes, then incubated with human IL-6 at 37°C for 15
15 minutes and incubated with 10 times as much of BD Phosflow Lyse/Fix Buffer as the
blood at 37°C for 12 minutes. Centrifugal separation was carried out at 5,884 m/s2 for
6 minutes with a centrifugal separator to precipitate the cells, and the supernatants were
removed.
The cell pellets were washed with 1 mL of phosphate buffered saline (PBS), then
20 incubated with 0.6 mL of BD Phosflow Perm Buffer III on ice for 30 minutes and
centrifuged at 5,884 m/s2 for 6 minutes by means of a centrifugal separator to
precipitate the cells, and the supernatants were removed.
The cell pellets were washed with 0.3 mL of BD Pharmingen Stain Buffer and
incubated with 0.1 mL of BD Pharmingen Stain Buffer, 10 L of BD Phosflow STAT-1
25 and 5 L of FITC-hCD3 at room temperature for 30 minutes. After addition of 0.1 mL
of BD Pharmingen Stain Buffer, the cells were centrifuged at 5,884 m/s2 for 6 minutes
by means of a centrifugal separator to precipitate the cells, and the supernatants were
removed.
The cell pellets were washed with 0.3 mL of BD Pharmingen Stain Buffer, and
30 0.12 mL of BD Pharmingen Stain Buffer was added. The cytokine signaling inhibition
was measured with FACS CantoII (manufactured by BD) by detecting FITC-labeled
CD3 positive T cells and detecting the amount of phosphated STAT-1 protein in the cells
55
as the PE fluorescence. From the plot of the logarithm of a compound concentration
and inhibitory activity, the IC50 value was calculated. The results of human whole blood
signal assays of the compounds of Synthetic Examples 3 to 7 are shown in Table 4.
[TABLE4]
5
Excellent inhibitory activity in the human whole blood signal assay is favorable for
high effectiveness against diseases against which inhibition of JAK is effective,
especially rheumatoid arthritis.
The compounds of the present invention showed excellent inhibitory activities
against JAK signaling by cytokine stimulation in human whole blood by means of th10 e
JAK inhibitory activity.
Further, the results of the human whole blood signal assay of Compound E
(Exampleb 20), Compound F (Exampleb 69), Compound G (Exampleb 70)), Compound
H (Exampleb 106)), Compound I(Exampleb 107) and Compound J (Exampleb 86)
15 disclosed in WO2013/024895 are shown In Table 5.
56
[TABLE5]
4. Inhibition of proliferation of erythro-leukemic cell line
The inhibitory activity of the compounds of the present invention on cell
proliferation mediated by JAK signal can be assayed using a human erythro-leukemi5 c
cell line, TF-1.
TF-1 cells (ATCC(American Type Culture Collection)) can be expanded in
RPMI1640 media containing 5% fetal bovine serum (hereinafter referred to as FBS) and
1 ng/mL GM-CSF (Granulocyte Macrophage Colony-Stimulating Factor) using a CO2
10 incubator (5 vol% CO2, 37 C). At the assay, TF-1 cells washed by PBS (Phosphate
Buffered Saline) are resuspended in RPMI1640 media containing 5% FBS and seeded
on 96-well culture plate at 1×104 cells/well. Then, a compound is added to each well of
the culture plate, and the cells are incubated at 37 C for 30 minutes. Then, cytokine
such as IL-4 or IL-6 is added, and the cells are incubated in a CO2 incubator (5 vol%
15 CO2, 37 C) for 3 days.
Cell proliferation can be assayed using WST-8 reagent (Kishida Chemical Co.,
Ltd.) according to instructions by the manufacturer. WST-8 reagent is added to each
well of the culture plate, and the cells are incubated in a CO2 incubator (5 vol% CO2,
37 C) for 4 hours. The generated formazan pigment is detected by measuring the
20 absorbance at 450 nm with a microplate reader. From the plot of logarithm of the
compound concentrations and the inhibitory activities, the IC50 value can be calculated.
5. Oral absorption property
A compound having oral absorption property is preferred for treatment of diseases
against which JAK inhibition is effective, and the oral absorption property of the
25 compounds of the present invention may be measured using rats as follows.
A compound is suspended in 0.5% methyl cellulose at a concentration of 0.6
57
mg/mL, and the suspension is forcibly administered orally by a feeding needle to a
female Lewis rat (CHARLES RIVER LABORATORIES JAPAN INC.) at a dose of 3
mg/kg/5 mL. Then, blood is sequentially collected through the jugular vein after
administration of the compound (after 0.5 to 8 hours) using heparin as an anticoagulant.
The collected blood is centrifuged at 17,652 m/s2 for 10 minutes by means of 5 a
centrifugal separator to obtain plasma. The plasma is analyzed by liquid
chromatography tandem mass spectrometry (LC/MS/MS, manufactured by Waters) to
calculate the transition of the concentration of the compound in the plasma after the oral
administration (after 0.5 to 8 hours).
10 6. Effect in collagen-induced rat arthritis model
To confirm the therapeutic effect on particularly rheumatoid arthritis among
diseases against which JAK inhibition is effective with an experimental animal model, a
collagen-induced rat arthritis model may be used (Prostaglandin & other Lipid Mediators,
2001, 66, pp. 317-327) as follows.
15 Bovine II types collagen solution (Chondrex, Inc.) and incomplete Freund’s
adjuvant (Difco) are mixed in equal amounts and emulsified to prepare an immune
solution. Then, the immune solution is intracutaneously administered to a Lewis
female rat (CHARLES RIVER LABORATORIES JAPAN INC.) at 4 portions on the back
and one portion on the tail root portion at a dose of 100 µL/portion using a Hamilton
20 syringe. 7 Days after administration of the immune solution, the immune solution is
intracutaneously administered similarly again.
The compound to be administered is suspended in 0.5% methyl cellulose at a
concentration optionally determined by the IC50 value of the cytokine signaling inhibition
obtained by the above 2. whole blood signal assay and the concentration of the
25 compound in the blood plasma obtained by the above 5. oral absorption property. The
compound suspension thus obtained is orally administered daily after the second
administration of the immune solution.
The thickness of the hind-paw swelling in 2 to 3 weeks after the second
administration of the immune solution is measured with a caliper to calculate the degree
30 of inhibition of arthritis by the compound.
Now, examples of formulations of compounds of the present invention. In the
Formulation Examples 1 to 5, Compound (A) means a compound represented by the
58
formula (I), the formula (II) or the formula (III).
FORMULATION EXAMPLE 1
A granule preparation containing the following ingredients is prepared.
Ingredients
Compound (A) 10 mg
Lactose 700 mg
Corn Starch 274 mg
HPC-L 16 mg
Total 1000 mg
A compound (A) and lactose are sifted through a 60-mesh sieve. Corn starch 5 is
sifted through a 120-mesh sieve. They are mixed in a V-type blender. The powder
mixture is kneaded with a low-viscosity hydroxypropylcellulose (HPC-L) aqueous
solution, granulated (extrusion granulation, die size 0.5-1 mm) and dried. The resulting
dry granules are sifted through a shaking sieve (12/60 mesh) to obtain a granule
10 preparation.
FORMULATION EXAMPLE 2
A powder preparation for capsulation containing the following ingredients is
prepared.
Ingredients
Compound (A) 10 mg
Lactose 79 mg
Corn Starch 10 mg
Magnesium Stearate 1 mg
Total 100 mg
15 A compound (A) and lactose are sifted through a 60-mesh sieve. Corn starch is
sifted through a 120-mesh sieve. They are mixed with magnesium stearate in a V-type
blender. The 10% powder is put in hard gelatin capsules No. 5, 100 mg each.
FORMULATION EXAMPLE 3
A granule preparation for capsulation containing the following ingredients is
20 prepared.
Ingredients
Compound (A) 15 mg
Lactose 90 mg
59
Corn Starch 42 mg
HPC-L 3 mg
Total 150 mg
A compound (A) and lactose are sifted through a 60-mesh sieve. Corn starch is
sifted through a 120-mesh sieve. They are mixed in a V-type blender. The powder
mixture is kneaded with a low-viscosity hydroxypropylcellulose (HPC-L) aqueous
solution, granulated and dried. The resulting dry granules are sifted through a shaking
sieve (12/60 mesh). The granules are put in hard gelatin capsules No. 4, 150 mg each5 .
FORMULATION EXAMPLE 4
A tablet preparation containing the following ingredients is prepared.
Ingredients
Compound (A) 10 mg
Lactose 90 mg
Microcrystalline cellulose 30 mg
Magnesium Stearate 5 mg
CMC-Na 15 mg
Total 150 mg
A compound (A), lactose, microcrystalline cellulose and CMC-Na
10 (carboxymethylcellulose sodium salt) are sifted through a 60-mesh sieve and mixed.
The powder mixture is mixed with magnesium stearate to give a bulk powder mixture.
The powder mixture is compressed directly into 150 mg tablets.
FORMULATION EXAMPLE 5
An intravenous preparation is prepared as follows.
Compound (A) 100 mg
Saturated Fatty Acid Glyceride 1000 ml
15 Solutions having the above-mentioned composition are usually administered to a
patient intravenously at a rate of 1 mL per 1 minute.
INDUSTRIAL APPLICABILITY
The compounds of the present invention have excellent JAK inhibitory activities
20 and are useful for prevention, treatment or improvement of autoimmune diseases,
especially rheumatoid arthritis, inflammatory diseases, allergic diseases, cancer and
leukemia.
60
The entire disclosures of Japanese Patent Application No. 2014-100712 filed on
May 14, 2014 including specification, claims and summary are incorporated herein by
reference in its entireties.
61

CLAIMS
1. A compound represented by the formula (I):
[wherein A1 is a C3-7 cycloalkylene group,
L1 is a C1-6 alkylene group5 ,
X1 is O or NH, and
when X1 is O, R1 is a C1-6 haloalkyl group, a cyano C1-6 haloalkyl group or a cyano C1-6
alkyl group, and
when X1 is NH, R1 is a cyano C1-6 haloalkyl group or a cyano C1-6 alkyl group], a
10 tautomer or pharmaceutically acceptable salt of the compound or a solvate thereof.
2. The compound according to Claim 1, wherein L1 is a methylene group, a tautomer
or pharmaceutically acceptable salt of the compound or a solvate thereof.
3. The compound according to Claim 1 or 2, wherein A1 is a cyclohexanediyl group,
a tautomer or pharmaceutically acceptable salt of the compound or a solvate thereof.
15 4. The compound according to any one of Claims 1 to 3, wherein X1 is O, a tautomer
or pharmaceutically acceptable salt of the compound or a solvate thereof.
5. The compound according to Claim 4, wherein R1 is a C1-4 haloalkyl group, a
tautomer or pharmaceutically acceptable salt of the compound or a solvate thereof.
6. The compound according to Claim 4, wherein R1 is a 3,3,3-trifluoropropyl group, a
20 tautomer or pharmaceutically acceptable salt of the compound or a solvate thereof.
7. 1-{trans-4-[(3,3,3-Trifluoropropoxy)methyl]cyclohexyl}-1Hpyrrolo[
3’,2’:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione, a tautomer or
pharmaceutically acceptable salt of the compound or a solvate thereof.
8. The compound according to any one of Claims 1 to 3, wherein X1 is NH, a
25 tautomer or pharmaceutically acceptable salt of the compound or a solvate thereof.
9. The compound according to Claim 8, wherein R1 is a cyano C1-4 haloalkyl group, a
tautomer or pharmaceutically acceptable salt of the compound or a solvate thereof.
10. The compound according to Claim 8, wherein R1 is a 3-cyano-1,1,1-
trifluoropropan-2-yl group, a tautomer or pharmaceutically acceptable salt of the
62
compound or a solvate thereof.
11. 3-({[trans-4-(2,4-Dioxo-2,3,4,7-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,3-
d]pyrimidin-1-yl)cyclohexyl]methyl}amino)-4,4,4-trifluorobutanenitrile, a tautomer or
pharmaceutically acceptable salt of the compound or a solvate thereof.
12. (R)-3-({[trans-4-(2,4-Dioxo-2,3,4,7-tetrahydro-1H-pyrrolo[3’,2’:5,6]pyrido[4,35 -
d]pyrimidin-1-yl)cyclohexyl]methyl}amino)-4,4,4-trifluorobutanenitrile, a tautomer or
pharmaceutically acceptable salt of the compound or a solvate thereof.
13. A compound represented by the formula (II):
10 [wherein A2 is a C3-7 cycloalkylene group,
L2 is a C1-6 alkylene group, and
R2 is a 5 to 10-membered aromatic heterocyclic group (the heterocyclic group may be
substituted with one or two identical or different substituents independently selected
from the group consisting of halogen atoms, C1-4 alkyl groups and C1-4 haloalkyl
15 groups)], a tautomer or pharmaceutically acceptable salt of the compound or a solvate
thereof.
14. The compound according to Claim 13, wherein L2 is a methylene group, a
tautomer or pharmaceutically acceptable salt of the compound or a solvate thereof.
15. The compound according to Claim 13 or 14, wherein A2 is a cyclohexanediyl
20 group, a tautomer or pharmaceutically acceptable salt of the compound or a solvate
thereof.
16. The compound according to any one of Claims 13 to 15, wherein R2 is a 5 to 6-
membered nitrogen-containing aromatic heterocyclic group (the heterocyclic group may
be substituted with one or two identical or different substituents independently selected
25 from the group consisting of halogen atoms, methyl groups and trifluoromethyl groups),
a tautomer or pharmaceutically acceptable salt of the compound or a solvate thereof.
17. The compound according to any one of Claims 13 to 16, wherein R2 is a pyrazolyl
group (the pyrazolyl group may be substituted with one or two identical or different
substituents independently selected from the group consisting of halogen atoms, methyl
63
groups and trifluoromethyl groups), a tautomer or pharmaceutically acceptable salt of
the compound or a solvate thereof.
18. 1-{trans-4-[(4-Methyl-1H-pyrazol-1-yl)methyl]cyclohexyl}-1H-pyrrolo[2,3-
h][1,6]naphthyridin-4(7H)-one, a tautomer or pharmaceutically acceptable salt of the
compound or a solvate thereof5 .
19. A compound represented by the formula (III):
[wherein A3 is a C3-7 cycloalkylene group,
L3 is a C1-6 alkylene group,
10 X3 is O or NH, and
when X3 is O, R3 is a C1-6 haloalkyl group, a cyano C1-6 haloalkyl group or a cyano C1-6
alkyl group, and
when X3 is NH, R3 is a cyano C1-6 haloalkyl group or a cyano C1-6 alkyl group], a
tautomer or pharmaceutically acceptable salt of the compound or a solvate thereof.
15 20. The compound according to Claim 19, wherein L3 is a methylene group, a
tautomer or pharmaceutically acceptable salt of the compound or a solvate thereof.
21. The compound according to Claim 19 or 20, wherein A3 is a cyclohexanediyl
group, a tautomer or pharmaceutically acceptable salt of the compound or a solvate
thereof.
20 22. The compound according to any one of Claims 19 to 21, wherein X3 is O, a
tautomer or pharmaceutically acceptable salt of the compound or a solvate thereof.
23. The compound according to Claim 22, wherein R3 is a C1-4 haloalkyl group or a
cyano C1-4 haloalkyl group, a tautomer or pharmaceutically acceptable salt of the
compound or a solvate thereof.
25 24. The compound according to Claim 22, wherein R3 is a 2,2,2-trifluoroethyl group or
a 3,3,3-trifluoropropyl group, a tautomer or pharmaceutically acceptable salt of the
compound or a solvate thereof.
25. The compound according to Claim 22, wherein R3 is a 3-cyano-1,1,1-
trifluoropropan-2-yl group or a 2-cyano-1,1,1-trifluoropropan-2-yl group, a tautomer or
64
pharmaceutically acceptable salt of the compound or a solvate thereof.
26. 1-{trans-4-[(2,2,2-Trifluoroethoxy)methyl]cyclohexyl}-1H-pyrrolo[2,3-
h][1,6]naphthyridin-4(7H)-one, a tautomer or pharmaceutically acceptable salt of the
compound or a solvate thereof.
27. 1-{trans-4-[(3,3,3-Trifluoropropoxy)methyl]cyclohexyl}-1H-pyrrolo[2,35 -
h][1,6]naphthyridin-4(7H)-one, a tautomer or pharmaceutically acceptable salt of the
compound or a solvate thereof.
28. 4,4,4-Trifluoro-3-{[trans-4-(4-oxo-4,7-dihydro-1H-pyrrolo[2,3-h][1,6]naphthyridin-1-
yl)cyclohexyl]methoxy}butanenitrile, a tautomer or pharmaceutically acceptable salt of
10 the compound or a solvate thereof.
29. (R)-4,4,4-Trifluoro-3-{[trans-4-(4-oxo-4,7-dihydro-1H-pyrrolo[2,3-
h][1,6]naphthyridin-1-yl)cyclohexyl]methoxy}butanenitrile, a tautomer or
pharmaceutically acceptable salt of the compound or a solvate thereof.
30. The compound according to any one of Claims 19 to 21, wherein X3 is NH, a
15 tautomer or pharmaceutically acceptable salt of the compound or a solvate thereof.
31. The compound according to Claim 30, wherein R3 is a cyano C1-4 haloalkyl group,
a tautomer or pharmaceutically acceptable salt of the compound or a solvate thereof.
32. The compound according to Claim 30, wherein R3 is a 3-cyano-1,1,1-
trifluoropropan-2-yl group, a tautomer or pharmaceutically acceptable salt of the
20 compound or a solvate thereof.
33. 4,4,4-Trifluoro-3-({[trans-4-(4-oxo-4,7-dihydro-1H-pyrrolo[2,3-h][1,6]naphthyridin-1-
yl)cyclohexyl]methyl}amino)butanenitrile, a tautomer or pharmaceutically acceptable salt
of the compound or a solvate thereof.
34. (R)-4,4,4-Trifluoro-3-({[trans-4-(4-oxo-4,7-dihydro-1H-pyrrolo[2,3-
25 h][1,6]naphthyridin-1-yl)cyclohexyl]methyl}amino)butanenitrile, a tautomer or
pharmaceutically acceptable salt of the compound or a solvate thereof.
35. A JAK inhibitor containing the compound as defined in any one of Claims 1 to 34,
a tautomer or a pharmaceutically acceptable salt of the compound or a solvate thereof,
as an active ingredient.
30 36. A preventive, therapeutic or improving agent for diseases against which inhibition
of JAK is effective, which contains the compound as defined in any one of Claims 1 to
34, a tautomer or pharmaceutically acceptable salt of the compound or a solvate thereof, as an active ingredient.
37. A therapeutic agent for rheumatoid arthritis, which contains the compound as
defined in any one of Claims 1 to 34, a tautomer or pharmaceutically acceptable salt of
the compound or a solvate thereof, as an active ingredient.
38. Medicament containing the compound as defined in any one of Claims 1 to 34, a
tautomer or a pharmaceutically acceptable salt of the compound or a solvate thereof, as
an active ingredient.